Defining angioinvasion and lymphatic invasion in papillary thyroid carcinoma: morphological criteria, utility of D2-40/CD31/ERG immunohistochemistry and correlation with clinicopathological characteristics.

AIMS: While CAP and ICCR protocols mandate the separation of angioinvasion (AI) and lymphatic invasion (LI) in thyroid carcinoma, distinction between them can be difficult. Because the presence of AI is used to stratify patients with papillary thyroid carcinoma (PTC), there is a need to accurately diagnose AI and LI. METHODS AND RESULTS: AI and LI were evaluated in 162 cases of PTC (n = 155) and high-grade differentiated thyroid carcinoma, papillary phenotype (HGDTCp, n = seven) using haematoxylin and eosin (H&E), D2-40 and CD31/ERG. In encapsulated carcinomas, vascular invasion (VI) was only of AI nature. Infiltrative carcinomas showed LI (46 of 131, 35%) and AI (19 of 131, 16%). The frequency of nodal metastasis (NM) and large volume of NM was 93 and 85%, respectively, in tumours with LI, and 39 and 26%, respectively, in those without LI. Luminal red blood cells and smooth muscle in the wall of large-calibre vessels were not reliable criteria to exclude LI and were seen in 23 and 6% of LI, respectively. LI was an independent predictor for NM, whereas AI is an independent predictor for distant metastasis at presentation in PTC/HGDTCp. CONCLUSION: VI in encapsulated carcinomas, including follicular variant PTC, is only of AI nature, confirming the position of this variant as a close entity to follicular carcinoma rather than classic PTC, whereas infiltrative PTC/HGDTCp may have LI or, less frequently, AI. As no morphological features reliably distinguish LI from AI, D2-40 and CD31/ERG immunostains should be considered for separating AI from LI when dealing with vascular invasion in an infiltrative PTC.

Histological prognosticators in neoadjuvant naive oesophageal cancer patients.

PURPOSE: Prognosis of oesophageal cancer is primarily based upon the TNM stage of the disease. However, even in those with similar TNM staging, survival can be varied. Additional histopathological factors including venous invasion (VI), lymphatic invasion (LI) and perineural invasion (PNI) have been identified as prognostic markers yet are not part of TNM classification. The aim of this study is to determine the prognostic importance of these factors and overall survival in patients with oesophageal or junctional cancer who underwent transthoracic oesophagectomy as the unimodality treatment. METHODS: Data from patients who underwent transthoracic oesophagectomy for adenocarcinoma without neoadjuvant treatment were reviewed. Patients were treated with radical resection, with a curative intent using a transthoracic Ivor Lewis or three staged McKeown approach. RESULTS: A total of 172 patients were included. Survival was poorer when VI, LI and PNI were present (p<0.001), with the estimated survival being significantly worse (p<0.001) when patients were stratified according to the number of factors present. Univariable analysis of factors revealed VI, LI and PNI were all associated with survival. Presence of LI was independently predictive of incorrect staging/upstaging in multivariable logistic regression analysis (OR 12.9 95% CI 3.6-46.6, p<0.001). CONCLUSION: Histological factors of VI, LI and PNI are markers of aggressive disease and may have a role in prognostication and decision-making prior to treatment. The presence of LI as an independent marker of upstaging could be a potential indication for the use of neoadjuvant treatment in patients with early clinical disease.

Type B2 vessels and infiltrative growth patterns b and c are associated with lymphatic invasion in pT1a-lamina propria mucosa esophageal squamous cell carcinoma.

BACKGROUND: Tumor growth pattern correlates with outcomes in patients with esophageal squamous cell carcinoma (ESCC), however, the clinical significance of the tumor growth pattern in pT1a-lamina propria mucosa (LPM) type of ESCC was unclear. This study was conducted to clarify clinicopathological features of tumor growth patterns in pT1a-LPM type ESCC and the relationship between tumor growth patterns and magnifying endoscopic findings. METHODS: Eighty-seven lesions diagnosed as pT1a-LPM ESCC were included. Clinicopathological findings including tumor growth pattern and narrow band imaging with magnifying endoscopy (NBI-ME) in the LPM area were investigated. RESULTS: Eighty-seven lesions were classified as infiltrative growth pattern-a (INF-a): expansive growth (n = 81), INF-b: intermediate growth (n = 4) and INF-c: infiltrative growth pattern (n = 2). Lymphatic invasion was shown in one INF-b and one INF-c lesion. NBI-ME and histopathological images were matched for 30 lesions. The microvascular pattern was classified into types B1 (n = 23) and B2 (n = 7) using the JES classification. All 23 type B1 lesions were classified as INF-a without lymphatic invasion. Type B2 lesions were classified as INF-a (n = 2), INF-b (n = 4) and INF-c (n = 1), and lymphatic invasion was present in two lesions (INF-b and INF-c). The rate of lymphatic invasion was significantly higher in type B2 than type B1 (p = 0.048). CONCLUSIONS: The tumor growth pattern of pT1a-LPM ESCC was mostly INF-a in type B1 patterns. Type B2 patterns are rarely present in pT1a-LPM ESCC, however lymphatic invasion with INF-b or INF-c was frequently observed. Careful observation before endoscopic resection with NBI-ME is important to identify B2 patterns to predict histopathology.

The prognostic value of separate lymphatic invasion and vascular invasion in oesophageal squamous cell carcinoma: a meta-analysis and systematic review.

BACKGROUND: Lymphovascular invasion (LVI) is a factor correlated with a poor prognosis in oesophageal squamous cell carcinoma (ESCC). Lymphatic invasion (LI) and vascular invasion (VI) should be reported separately because they may indicate a difference in prognosis. The prognostic role of LI and VI in ESCC patients remains controversial. A meta-analysis was conducted to resolve this question. METHODS: We searched the PubMed, EMBASE, Web of Science, Scopus and Cochrane Library databases for studies on the association between LI and VI and the prognosis of patients with ESCC. The PICOs (Participant, Intervention, Comparison, Outcome) strategy were selected for the systematic review and meta-analysis. The effect size (ES) was the hazard ratio (HR) or relative ratio (RR) with 95% confidence intervals (CI) for overall survival (OS) and recurrence-free survival (RFS). RESULTS: A total of 27 studies with 5740 patients were included. We calculated the pooled results from univariate and multivariate analysis using the Cox proportional hazards method. The heterogeneity was acceptable in OS and RFS. According to the pooled results of multivariate analysis, both LI and VI were correlated with a worse OS. VI was a negative indicator for RFS, while the p value of VI was greater than 0.05. The prognostic role was weakened in subgroup analysis with studies using haematoxylin-eosin staining method. CONCLUSIONS: Both LI and VI were indicators of a worse OS outcome. LI was a more significant indicator in predicting a worse RFS. More larger sample studies with immunohistochemical staining and good designs are required to detect the prognostic value of separate LI and VI in ESCC.

Lymphatic invasion is a prognostic factor of pathological N0 esophageal squamous cell carcinoma.

Adjuvant treatment after upfront esophagectomy for esophageal squamous cell carcinoma (ESCC) is indicated only for patients with lymph node metastasis in Japan. However, the recurrence rate after curative resection is high even for node-negative patients; thus, understanding the prognostic factors for patients with node-negative ESCC, which still remains unidentified, is important. Here, we aimed to reveal the prognostic factors for the long-term outcomes of patients with node-negative ESCC. Moreover, we compared the long-term outcomes among high-risk node-negative and node-positive patients. This single-institution retrospective study included 103 patients with pT1b-3N0 ESCC who underwent upfront surgery to identify the population at a high risk of recurrence. To compare overall survival (OS) and recurrence-free survival (RFS) between high-risk node-negative and node-positive patients, 51 node-positive ESCC patients with pStage IIIA or less who had undergone upfront surgery were also included. Univariable and multivariable analyses were performed using the Cox proportional hazard regression model. OS and RFS were compared using the log-rank test. Only lymphatic invasion (Ly+) was associated with worse 3-year OS (hazard ratio, 8.63; 95% confidence interval, 2.09-35.69; P = 0.0029) and RFS (hazard ratio, 4.87; 95% confidence interval, 1.69-14.02; P = 0.0034). The node-negative and Ly+ patients showed significantly worse OS (P = 0.0242) and RFS (P = 0.0114) than the node-positive patients who underwent chemotherapy. Ly+ is the only independent prognostic factor in patients with node-negative ESCC. Patients with node-negative and Ly+ ESCC may benefit from adjuvant treatment.

The role of vascular invasion and lymphatic invasion in predicting recurrent thoracic oesophageal squamous cell carcinoma.

BACKGROUND: Numerous studies have addressed lymphovascular invasion (LVI) in patients with thoracic oesophageal squamous cell carcinoma (ESCC); however, little is known about the individual roles of lymphatic invasion (LI) and vascular invasion (VI). We aimed to analyse the prognostic significance of LI and VI in patients with thoracic ESCC from a single centre. METHODS: This retrospective study included 396 patients with thoracic ESCC who underwent oesophagectomy and lymphadenectomy in our hospital. The relationship between LI, VI and the other clinical features was analysed, and disease-free survival (DFS) was calculated. Survival analysis was performed by univariate and multivariate statistics. RESULTS: Briefly, VI and LI were present in 25.8% (102 of 396) and 23.7% (94 of 396) of ESCC patients, respectively, with 9.15% patients presenting both LI and VI; the remaining patients did not present LI or VI. We found that LI was significantly associated with pN stage (P<0.001) and pTNM stage (P<0.001), and similar results were found in VI. Moreover, survival analysis showed that pT stage (P<0.001), pN stage (P=0.001), pTNM stage (p<0.001), VI (P=0.001) and LI (P<0.001) were associated with DFS in ESCC. Furthermore, multivariate analysis suggested that pT stage (RR=1.4, P =0.032), pN stage (RR=1.9, P<0.001) and LI (RR=1.5, P=0.008) were independent predictive factors for DFS. Finally, relapse was observed in 110 patients (lymph node metastasis, 78 and distant, 32) and 147 patients with cancer-related deaths. Subanalysis showed that LI-positive patients had higher lymph node metastasis, although there was no significant difference (32.1% vs. 15.6%, P=0.100). CONCLUSIONS: LI and VI were common in ESCC; they were all survival predictors for patients with ESCC, and LI was independent. Patients with positive LI were more likely to suffer lymph node metastasis.

Prognostic significance of intrahepatic lymphatic invasion in colorectal liver metastases.

BACKGROUND: Intrahepatic lymphatic invasion is an adverse prognostic factor after hepatectomy for colorectal liver metastases (CLMs). However, most patients in previous reports had liver resection before the era of FOLFOX/FIRI-based chemotherapy. METHODS: Forty-six patients who underwent hepatectomy for CLMs from 2004 to 2020 were evaluated. We histologically evaluated portal invasion, intrahepatic lymphatic invasion, and biliary invasion on hematoxylin-eosin slides. We also collected the following clinicopathologic factors: gender, age, timing, the number and maximum size of CLMs, preoperative tumor markers, neutrophil/lymphocyte ratio, location, and lymph node metastases of primary cancer, and chemotherapy after hepatectomy. A multivariate Cox proportional hazard model was used to define the relationship between overall (OS) or disease-free survival (DFS) and clinicopathologic factors. RESULTS: Histological invasions were portal invasion in 8 (17.4 %), intrahepatic lymphatic invasion in 6 (13.0 %), and biliary invasion in 5 (10.9 %). Chemotherapy for recurrence after hepatectomy (n = 29) was performed in 22 and 14 of those who received FOLFOX/FIRI-based chemotherapy. By multivariate analysis, the number of CLMs (p < 0. 01) and presence of intrahepatic lymphatic invasion (p = 0.02) were independent predictors of recurrence. The number of CLMs (p = 0.02) and prehepatectomy carcinoembryonic antigen level (p = 0.02), but not intrahepatic lymphatic invasion (p = 0.18), were independent predictors of survival using multivariate analysis. CONCLUSIONS: The presence of intrahepatic lymphatic invasion adversely affected patient's DFS, but not OS in patients with CLMs in the era of FOLFOX/FIRI chemotherapy. FOLFOX/FIRI-based chemotherapy might improve OS, even in patients with positive intrahepatic lymphatic invasion.

Metastatic risk profile of microscopic lymphatic and venous invasion in papillary thyroid cancer.

OBJECTIVES: The aim of this study was to define the suitability of microscopic lymphatic and venous invasion for prediction of lymph node and distant metastases in papillary thyroid cancer. DESIGN: Stratification by microscopic lymphatic and venous invasion, and multivariable analyses on lymph node and distant metastases including microscopic lymphatic and venous invasion as independent variables. SETTING: Tertiary referral centre. PARTICIPANTS: 422 patients who had ≥5 lymph nodes removed at initial thyroidectomy. MAIN OUTCOME MEASURES: Lymph node and distant metastases. RESULTS: Patients with microscopic lymphatic invasion had larger primary tumours than patients without and more often revealed microscopic venous invasion, multifocal tumour growth and lymph node metastases. Patients with microscopic venous invasion exhibited larger primary tumours than patients without and more commonly had microscopic lymphatic invasion, poor tumour differentiation, lymph node metastases and distant metastases. Prediction of lymph node metastases by microscopic lymphatic invasion was better than prediction of distant metastases by microscopic venous invasion regarding sensitivity (61.0 vs. 33.3%) and positive predictive value (92.6 vs. 20.9%), comparable regarding specificity (89.6 and 93.4%), and worse regarding negative predictive value (51.9 vs. 95.3%) and accuracy (70.1 vs. 87.7%). On multivariable logistic regression analysis, microscopic lymphatic invasion was associated with lymph node metastasis (odds ratio [OR] 11.1) and multifocal tumour growth (OR 2.4), whereas primary tumour size (OR 5.8 for tumours >40 mm relative to tumours ≤20 mm) and multifocal tumour growth (OR 3.1) were associated with distant metastasis. CONCLUSION: Stricter histopathological criteria are warranted to enhance the utility of microscopic vascular invasion for prediction of distant metastases in papillary thyroid cancer.

Transcriptome of CD8+ tumor-infiltrating T cells: a link between diabetes and colorectal cancer.

There is an increased risk of colorectal cancer (CRC) development in patients with non-insulin-dependent type 2 diabetes. CD8+ T cells have been implicated in diabetes and are crucial for anti-tumor immunity. However, transcriptomic profiling for CD8+ T cells from CRC diabetic patients has not been explored. We performed RNA sequencing and compared transcriptomic profiles of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in CRC diabetic patients with CRC nondiabetic patients. We found that genes associated with ribogenesis, epigenetic regulations, oxidative phosphorylation and cell cycle arrest were upregulated in CD8+ TILs from diabetic patients, while genes associated with PI3K signaling pathway, cytokine response and response to lipids were downregulated. Among the significantly deregulated 1009 genes, 342 (186 upregulated and 156 downregulated) genes were selected based on their link to diabetes, and their associations with the presence of specific CRC pathological parameters were assessed using GDC TCGA colon database. The 186 upregulated genes were associated with the presence of colon polyps history (P = 0.0007) and lymphatic invasion (P = 0.0025). Moreover, CRC patients with high expression of the 186 genes were more likely to have poorer disease-specific survival (DSS) (Mantel-Cox log-rank P = 0.024) than those with low score. Our data provide novel insights into molecular pathways and biological functions, which could be altered in CD8+ TILs from CRC diabetic versus nondiabetic patients, and reveal candidate genes linked to diabetes, which could predict DSS and pathological parameters associated with CRC progression. However, further investigations using larger patient cohorts and functional studies are required to validate these findings.

The risk of lymph node metastasis in gastric cancer conforming to indications of endoscopic resection and pylorus-preserving gastrectomy: a single-center retrospective study.

BACKGROUND: Lymph node metastasis (LNM) status is an important prognostic factor that strongly influences the treatment decision of early gastric cancer (EGC). This study aimed to evaluate the pattern and clinical significance of LNM in EGC. METHODS: A total of 354 patients with carcinoma in situ (n = 42), EGC (n = 312) who underwent radical gastrectomy were enrolled. Their clinicopathological features, pathological reports, and prognostic data were collected and analyzed. RESULTS: The incidence of LNM in all patients was 18.36% (65/354). The rates of D1 and D2 station metastases were 12.10% (43/354) and 6.21% (22/354), respectively. The rates of LNM in absolute indication of endoscopic resection and expanded indication were 3.27% (2/61) and 28.55% (4/14), respectively. Skip LNM was observed in 3.67% (13/354) of patients. For those with middle-third tumor, the metastasis rate of the No. 5 lymph node was 3.05% (5/164). The independent risk factors for LNM were tumors measuring > 30 mm, poorly differentiated tumors, and lymphovascular invasion (all P < 0.05; area under the curve, 0.783). The 5-year disease-free survival rates of patients with and without LNM were 96.26 and 79.17%, respectively (P = 0.011). Tumors measuring > 20 mm and LNM were independent predictive factors for poor survival outcome in all patients. CONCLUSIONS: Patients with EGC conforming to expanded indications have a relatively high risk of LNM and may not be suitable for endoscopic submucosal dissection. Pylorus-preserving gastrectomy for patients with middle-third EGC remains controversial due to the high metastasis rate of the No. 5 lymph node.

Lymphovascular invasion in breast cancer is associated with gene expression signatures of cell proliferation but not lymphangiogenesis or immune response.

BACKGROUND: While the prognostic relevance of lymphovascular invasion (LVI) in breast cancer is well known, its molecular biology is poorly understood. We hypothesized that pathologically determined LVI reflects molecular features of tumors and can be discerned from their genomic and transcriptomic profiles. METHODS: LVI status and Nottingham histological scores of primary breast tumors of The Cancer Genome Atlas (TCGA) project were assessed from pathology reports; other clinical and molecular data were obtained from TCGA data portals and publications. Two independent datasets (GSE5460 and GSE7849) were combined and used for validation. RESULTS: LVI status was determinable for 639 and 196 cases of the TCGA and validation cohorts, among whom LVI incidence was 37.8% and 37.2%, respectively. LVI was associated with high tumor Ki67 expression, advanced pathologic stage, and high Nottingham scores. LVI-positive cases had worse overall and progression-free survival regardless of cancer subtype. Surprisingly, in both cohorts, LVI was not associated with lymphangiogenesis or lymphatic vessel density as estimated from tumor expression of lymphatic endothelium-associated genes. LVI-positive tumors had higher genome copy number aberrations, aneuploidy, and homologous recombination defects, but not single-nucleotide variations or intra-tumor genome heterogeneity. Tumor immune cell composition and cytolytic activity was not associated with LVI status. On the other hand, expression of cell proliferation-related genes was significantly increased in LVI-positive tumors. CONCLUSION: Our study suggests that breast cancer with LVI is a highly proliferative cancer, and it does not correlate with gene expression markers for lymphangiogenesis or immune response.

Clinical significance of lymphatic invasion in the esophageal region in patients with adenocarcinoma of the esophagogastric junction.

BACKGROUND AND OBJECTIVES: The lymphatic flow around the esophagogastric junction is complicated. Therefore, it is unclear whether lymphatic invasion in the esophageal region (eLI) and in the gastric region (gLI) in patients with adenocarcinoma of the esophagogastric junction (AEG) equally affect the incidence of lymph node metastases (LNM), and consequently, survival. METHODS: We retrospectively reviewed clinicopathological data of 175 patients with AEG between January 2008 and July 2017. Risk factors for LNM and impacts of eLI or gLI on survival outcomes were investigated. RESULTS: eLI was identified in 34% of the patients (59/175). By multivariate analysis, eLI was associated with an increased risk of both mediastinal LNM (odds ratio [OR] = 2.98, 95% confidence interval [CI]: 1.26-7.05) and abdominal LNM (OR = 5.44, 95% CI: 1.95-15.20). The 5-year overall survival for patients with eLI (53%) was significantly worse than for patients without eLI (76%) (hazard ratio = 2.45, 95% CI: 1.37-10.01). gLI was not selected in either of these analyses. CONCLUSIONS: Positive eLI was strongly associated with mediastinal and abdominal LNM and worse survival in patients with AEG compared with gLI. In the histopathological examination, it seems to make sense to assess eLI and gLI separately.

The significance of micro-lymphatic invasion and pathological Gleason score in prostate cancer patients with pathologically organ-confined disease and negative surgical margins after robot-assisted radical prostatectomy.

BACKGROUND: The development process of recurrence in prostate cancer patients with pathologically organ-confined (pT2) disease and negative surgical margins is unclear. The aim of the present study was to determine factors associated with the development of biochemical recurrence following robot-assisted radical prostatectomy among those prostate cancer patients. METHODS: We retrospectively reviewed the data of patients who underwent robot-assisted radical prostatectomy without neoadjuvant endocrine therapy. We evaluated prognostic factors in 1096 prostate cancer patients with pT2 disease and negative surgical margins. Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent predictors for biochemical recurrence. RESULTS: Of the 1096 patients, 55 experienced biochemical recurrence during the follow-up period. The 5-year biochemical recurrence-free survival rate for patients with pT2 and negative surgical margins was 91.8%. On univariate analysis, clinical stage, biopsy Gleason score, percent of positive core, pathological Gleason score, and the presence of micro-lymphatic invasion were significantly associated with biochemical recurrence. On a multivariate analysis, the presence of micro-lymphatic invasion and a pathological Gleason score ≥ 4 + 3 were significant prognostic factors for biochemical recurrence. Based on these factors, we developed a risk stratification model. The biochemical recurrence-free survival rate differed significantly among the risk groups. CONCLUSIONS: The prognosis of prostate cancer patients with pT2 disease and negative surgical margins is favorable. However, patients with the presence of micro-lymphatic invasion and a pathological Gleason score ≥ 4 + 3 tend to experience biochemical recurrence more often after surgery. Therefore, careful follow-up might be necessary for those patients.

Intramucosal-lymphatic invasion has a slight impact on lymph node metastasis in patients with early gastric cancer.

PURPOSE: Lymphatic invasion (LI) is associated with lymph node metastasis (LNM) and a poor prognosis in patients with early gastric cancer (EGC). Although the impact of the LI volume on LNM has been described, no reports have assessed the impact of its depth on LNM. METHODS: A total of 360 EGC patients with pathologically proven LI who underwent radical gastrectomy with lymphadenectomy between January 2005 and June 2018 at our institution were extracted from our database. Patients were divided into 2 groups: the mLI group, in which LI was limited to the muscularis mucosae (n = 34); and the smLI group, in which LI reached the submucosal region (n = 326). Clinicopathological features, including the LNM incidence, were compared between the groups. RESULTS: LNM was recognized in 3 patients (9%) in the mLI group and 101 (31%) in the smLI group (P = 0.005). In the mLI group, LNM was not recorded in any patients who met the curative criteria of ESD other than mLI. CONCLUSIONS: LI limited to the mucosal region does not seem to be a strong indicator for LNM. When pathological findings of an endoscopic submucosal dissection specimen show only mLI as a non-curative criterion, the probability of LNM may be very low.

Transcriptional profiling of breast cancer-associated lymphatic vessels reveals VCAM-1 as regulator of lymphatic invasion and permeability.

Tumor-associated lymphangiogenesis and lymphatic invasion of tumor cells correlate with poor outcome in many tumor types, including breast cancer. Various explanations for this correlation have been suggested in the past, including the promotion of lymphatic metastasis and an immune-inhibitory function of lymphatic endothelial cells (LECs). However, the molecular features of tumor-associated lymphatic vessels and their implications for tumor progression have been poorly characterized. Here, we report the first transcriptional analysis of tumor-associated LECs directly isolated from the primary tumor in an orthotopic mouse model of triple negative breast cancer (4T1). Gene expression analysis showed a strong upregulation of inflammation-associated genes, including endothelial adhesion molecules such as VCAM-1, in comparison to LECs derived from control tissue. In vitro experiments demonstrated that VCAM-1 is not involved in the adhesion of tumor cells to LECs but unexpectedly promoted lymphatic permeability by weakening of lymphatic junctions, most likely through a mechanism triggered by interactions with integrin α4 which was also induced in tumor-associated LECs. In line with this, in vivo blockade of VCAM-1 reduced lymphatic invasion of 4T1 cells. Taken together, our findings suggest that disruption of lymphatic junctions and increased permeability via tumor-induced lymphatic VCAM-1 expression may represent a new target to block lymphatic invasion and metastasis.

Phospho-Sphingosine Kinase 1 Expression in Lymphatic Spread of Esophageal Squamous Cell Carcinoma.

BACKGROUND: Lymphatic spread is the main mode of progression of esophageal squamous cell carcinoma (ESCC). Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator, which produced by sphingosine kinase 1 (SphK1) activated by phosphorylation. The SphK1-S1P axis has a crucial role in lymphangiogenesis. However, the significance of phospho-SphK1 (pSphK1) in the progression of ESCC has not been fully investigated. MATERIALS AND METHODS: We evaluated pSphK1 expression in 92 surgically resected tumor tissues of ESCC by the immunohistochemistry. Fifty-nine (64%) patients with moderate or strong expression and 33 (36%) with negative or weak expression were classified in the pSphK1-high and pSphK1-low groups, respectively. RESULTS: Higher pathological N category (pN) was more frequently observed in the pSphK1-high group (P < 0.01). The median number of lymph node metastasis (pSphK1-high: 2 versus pSphK1-low: 0; P < 0.01), the proportion of patients with lymphatic invasion (69% versus 18%; P < 0.01) and that with intramural metastasis (27% versus 3%; P < 0.01) were significantly higher in the pSphK1-high group. The presence of lymphatic invasion (odds ratio [OR] 5.63; P < 0.01) and pN1-3 (OR 3.26; P = 0.04) were independently associated with high pSphK1 expression. The 5-y overall survival rate of the pSphK1-high group was significantly lower than that of the pSphK1-low group (50.8% versus 67.3%; P = 0.01). High pSphK1 expression was not identified as a significant independent prognostic factor. CONCLUSIONS: We provide the first evidence of the association between high expression of pSphK1 and both lymphatic spread and patient outcomes in ESCC.

Inflammatory Breast Cancer: a Separate Entity.

PURPOSE OF REVIEW: Inflammatory breast cancer (IBC) is an uncommon but highly aggressive subtype of breast cancer that contributes significantly to breast cancer-related mortality. In this review, we provide an overview of the clinical and molecular characteristics of IBC, and highlight some areas of need for ongoing research. RECENT FINDINGS: The disease is characterized by florid tumor emboli that obstruct dermal lymphatics, leading to swelling and inflammation of the affected breast. Recent studies have focused on tumor cell intrinsic features, such as signaling through pathways involved in growth and stem-like behavior, as well as extrinsic features, such as the immune system, that can be leveraged to develop new potential therapies. Key efforts have led to an increase in awareness of the disease as well as new insights into IBC pathogenesis. However, there is a strong need for new therapies designed specifically for IBC, and many unanswered questions remain.

Implication of visceral obesity in patients with esophageal squamous cell carcinoma.

PURPOSE: Visceral obesity is considered to be associated not only with chronic systemic inflammation but also with aggressive cancer behavior. However, the implication of visceral obesity in patients with esophageal squamous cell carcinoma (ESCC) is unclear. METHODS: Computed tomography volumetry was performed in 364 patients who underwent esophagectomy for ESCC. We calculated the ratio of the visceral fat area to the subcutaneous fat area (VS ratio), which is a valuable parameter of visceral obesity. Then, the clinicopathological characteristics were compared between patients with low VS ratio and those with high VS ratio. RESULTS: Overall and disease-specific survivals of patients with high VS ratio were significantly worse than those with low VS ratio (P < 0.001 in both). Patients with high VS ratio had considerably more advanced pN factor, higher prevalence of lymphatic invasion, and more number of metastatic lymph nodes than those with low VS ratio (P = 0.044, < 0.001, and 0.006, respectively). Among patients who received preoperative treatment, high VS ratio correlated with poor response to preoperative treatment (P = 0.040). CONCLUSIONS: Visceral obesity was associated with lymphatic invasiveness and poor response to preoperative treatment in patients with ESCC, which may negatively influence their prognosis.

Prognostic value of CC-chemokine receptor seven expression in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitor.

BACKGROUND: CC-chemokine receptor seven (CCR7), a G-protein coupled receptor normally facilitating immune cells lymphatic homing, has recently been identified on several cancer cells in promoting invasion and lymphatic specific metastasis by mimicking normal leukocytes. As tyrosine kinase inhibitors for metastatic renal cell carcinoma (mRCC) mostly emphasized on vascular inhibition, whether the CCR7 expressing tumor cells with potential lymphatic invasion function could have an impact on mRCC patient's drug response and survival, was unknown. METHODS: In this study, in a clinical aspect, we retrospectively investigated the prognostic and predictive impact of tumoral CCR7 expression in 110 mRCC patients treated with sunitinib and sorafenib, and its correlation with pre- or post-administration lymphatic involvement. Immunohistochemistry on tissue microarrays were conducted for CCR7 expression evaluation. RESULTS: Kaplan-Meier and univariate analyses suggested high tumoral CCR7 expression as an adverse prognosticator for mRCC patients' overall survival (OS), which was further confirmed in the multivariate analyses (P = 0.002, P = 0.003 for bootstrap). This molecule could be combined with Heng's risk model for better patient OS prediction. High tumoral CCR7 expression was also an independent dismal predictor for patients' progression free survival (PFS) (P = 0.010, P = 0.013 for bootstrap), and correlated with poorer best drug response. Moreover, a possible correlation of CCR7 high expression and patients' baseline and post-administration lymph node metastasis was found. CONCLUSIONS: High tumoral CCR7 expression correlated with potential lymphatic involvement and poor prognosis of mRCC patients treated with tyrosine kinase inhibitors. Further external validations and basic researches were needed to confirm these results.

Lymphatic invasion predicts sentinel lymph node metastasis and adverse outcome in primary cutaneous melanoma.

BACKGROUND: Sentinel lymph node (SLN) metastasis is a powerful predictor of survival in primary cutaneous melanoma. Lymphatic invasion (LI) may correlate with increased risk of SLN metastasis. Intralymphatic metastases, often difficult to detect on hematoxylin and eosin (H&E) stained sections, are readily identified with dual immunohistochemistry for melanocytic and lymphatic markers. METHODS: We used dual S100/D240 immunohistochemistry to detect LI in 125 melanomas from patients who underwent SLN biopsy and correlated LI with melanoma staging parameters and disease status. RESULTS: Dual immunohistochemistry allowed for the identification of LI in 33 cases (26%), compared to only 2% on H&E stained sections. Melanomas with LI showed greater thickness, higher mitotic rate and more frequent ulceration. Eleven of 33 cases with LI (33%) and 10 of 92 cases without LI (11%) were associated with a positive SLN (P = .006). More patients without LI were disease-free at last follow-up (80%) than patients with LI (50%; P = .002); LI was significantly associated with decreased progression-free survival. CONCLUSION: The detection of LI is improved by dual immunohistochemistry and predicts SLN metastasis. The presence of LI may impact therapeutic planning in melanoma, such as the decision to perform a SLN biopsy.