Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion.

BACKGROUND: Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non-healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease-free survival (DFS), and overall survival (OS). METHODS: In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin-antithrombin (TAT) and D-dimer were correlated with clinicopathological data, and 5-year survival. RESULTS: Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D-dimer was higher in node positive (507 (CI: 411-625) ng/mL, n = 68) vs negative patients (428 (CI: 387-472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (≥3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT. CONCLUSION: This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.

Pre-operative Axillary Ultrasound-Guided Needle Sampling in Breast Cancer: Comparing the Sensitivity of Fine Needle Aspiration Cytology and Core Needle Biopsy.

BACKGROUND: Pre-operative ultrasound-guided needle sampling (UNS) of abnormal axillary lymph nodes in breast cancer can identify patients with axillary metastases and therefore rationalize patient care and inform decision-making. To obtain tissue diagnosis, UNS can be performed by either fine needle aspiration (FNA) or core needle biopsy (CNB). However, few studies have compared the sensitivity of these techniques and the majority show no difference. METHODS: All node-positive patients (those with micro- and macrometastases but not isolated tumor cells) treated at a tertiary referral center between January 2012 and December 2015 were retrospectively identified from pathology records. The result of the first axillary UNS performed on each patient was compared with postoperative histopathology results. The UNS method used was according to individual radiologist preference. RESULTS: A total of 215 patients underwent FNA (1 patient had bilateral breast cancer and underwent bilateral FNA), and 92 underwent CNB. Sensitivity of CNB was significantly higher than FNA (83.7 vs. 69.0%, P = 0.008). The false-negative rate in the FNA group was therefore higher than in the CNB group by a factor of 2.5. There was no difference in inadequacy rate between the two techniques. There were no complications in the FNA group, and only one hematoma (which did not require operative intervention) in the CNB group. CONCLUSIONS: CNB is safe and should be the preferred technique for UNS to improve sensitivity.

Prognostic significance of cancer within 1 mm of the circumferential resection margin in oesophageal cancer patients following neo-adjuvant chemotherapy.

OBJECTIVES: The prognostic significance of the circumferential resection margin (CRM) status in oesophageal cancer patients treated with neo-adjuvant chemotherapy and radical resection is controversial. Furthermore, it is currently unclear whether patients with cancer located at the CRM have a prognosis different from that of those with cancer within 1 mm of the CRM. This is the first study aiming to establish the optimal tumour-free distance from the CRM of an oesophagectomy in patients who have undergone neo-adjuvant chemotherapy. METHODS: The clinicopathological data of 232 oesophageal cancer patients from two UK centres were analysed. The CRM status was classified as Group A (cancer at the CRM), Group B (cancer within 1 mm but not at the CRM) and Group C (no cancer within 1 mm from the CRM). The relationship between the CRM status and patient survival was investigated. RESULTS: Thirty-eight specimens were classified as Group A, 89 as Group B and 105 as Group C. CRM status was related to the depth of tumour invasion (P < 0.001) and lymph node status (P < 0.001). The prognoses of the Group A and the Group B patients were similar. Both were poorer than that of the Group C patients (P = 0.008). Lymph node status was the only independent prognostic marker in multivariate analysis. CONCLUSIONS: Oesophageal cancer patients treated with preoperative chemotherapy with cancer cells at the CRM or within 1 mm of the CRM of the resected specimen have a significantly worse survival than patients with no cancer cells within 1 mm of the margin. However, this study suggests that the overall prognostic significance of the CRM status is limited in this cohort and the postoperative lymph node status is the most important prognostic factor in oesophageal cancer patients treated with neo-adjuvant chemotherapy and surgery.

Computed tomography overestimation of esophageal tumor length: Implications for radiotherapy planning.

AIM: To assess the relationship between preoperative computed tomography (CT) and postoperative pathological measurements of esophageal tumor length and the prognostic significance of CT tumor length data. METHODS: A retrospective study was carried out in 56 patients who underwent curative esophagogastrectomy. Tumor lengths were measured on the immediate preoperative CT and on the post-operative resection specimens. Inter- and intra-observer variations in CT measurements were assessed. Survival data were collected. RESULTS: There was a weak correlation between CT and pathological tumor length (r = 0.30, P = 0.025). CT lengths were longer than pathological lengths in 68% (38/56) of patients with a mean difference of 1.67 cm (95% CI: 1.18-2.97). The mean difference in measurements by two radiologists was 0.39 cm (95% CI: -0.59-1.44). The mean difference between repeat CT measured tumor length (intra-observer variation) were 0.04 cm (95% CI: -0.59-0.66) and 0.47 cm (95% CI: -0.53-1.47). When stratified, patients not receiving neoadjuvant chemotherapy showed a strong correlation between CT and pathological tumor length (r = 0.69, P = 0.0014, n = 37) than patients that did (r = 0.13, P = 0.43, n = 19). Median survival with CT tumor length > 5.6 cm was poorer than with smaller tumors, but the difference was not statistically significant. CONCLUSION: Esophageal tumor length assessed using CT does not reflect pathological tumor extent and should not be the only modality used for management decisions, particularly for planning radiotherapy.

Tumour budding and a low host inflammatory response are associated with a poor prognosis in oesophageal and gastro-oesophageal junction cancers.

AIMS: Tumour budding and host inflammatory response are parameters easily assessed histologically that have prognostic significance in many cancers. There have been few studies examining these parameters in oesophageal or gastro-oesophageal cancers. This study aims to address that deficiency. METHODS AND RESULTS: A two-centre, retrospective study was carried out on 356 patients. Tumour budding and host inflammatory response at the invasive front were assessed histologically. Statistical analysis was performed to determine the prognostic significance of these factors. The median number of tumour buds was four (range 0-50) with 172 of 356 cases having five or more buds at the invasive front. The presence of five or more buds was associated with a poor prognosis on univariate analysis (P = 0.0001), as was a sparse or moderate host inflammatory response (P = 0.001). Tumour budding retained prognostic significance when tumours were separated into adenocarcinomas (n = 287) and squamous cell carcinomas (n = 69), but host inflammatory response was a significant prognostic factor only for adenocarcinomas. On multivariate analysis the presence of five or more buds retained significance (P = 0.002). CONCLUSIONS: Tumour budding and host inflammatory response are important prognostic factors in patients with oesophageal/gastro-oesophageal cancer and can be used to identify high-risk patients who would benefit from closer follow-up and adjuvant therapies.

The influence of surgical excision margins on keloid prognosis.

Keloid disease is known to have variable clinical behavior in response to therapy and there is no clinicopathologic classification that predicts such varied behavior. The aim of this study was to study the effect of excision margins and other histopathologic characteristics on keloid prognosis.Seventy-five multiethnic patients presenting with keloid scars at a department of plastic and reconstructive surgery during an 11-year period were included in this study. Clinical data was collected and detailed histologic analyses using light microscopy were carried out on archived patient specimens.A detailed histopathologic examination of all tissue samples identified keloid border or margin characteristics which were classified into "circumscribed" (borders clearly-demarcated) and "infiltrative" (borders not clearly-demarcated and not easily-definable). The specific histologic findings were correlated with keloid recurrence which revealed that incomplete peripheral (P < 0.001) and deep excision margins (P < 0.001), as well as infiltrative borders (P < 0.05) were associated with higher 1-year reported recurrence rates.This study has given evidence that incomplete surgical excision are associated with higher recurrence and this may justify the practice of routine histopathologic reporting of keloid excision margins.

The degree of circumferential tumour involvement as a prognostic factor in oesophageal cancer.

OBJECTIVE: Tumour length is an adverse prognostic factor in oesophageal cancer. However, the prognostic role of the degree of oesophageal circumference (DOC) involved by tumour with or without resection margin invasion is not clear. This work assessed the relationship between DOC involved by tumour, clinico-pathological variables and prognosis. METHODS: The clinico-pathological details of 320 patients who underwent potentially curative oesophagogastrectomy for cancer between 1994 and 2007 were analysed. The DOC involved with tumour measured macroscopically on the resected specimen was classified as small (<2.5 cm, n = 115), large (> or = 2.5 cm, n = 144) or circumferential (i.e. involving the whole circumference, n = 61). Univariate and multivariate survival analyses were carried out. RESULTS: The DOC with tumour was higher in ulcerating tumours than stenosing or polypoidal types (p = 0.017). Tumour length, T-stage, neoadjuvant chemotherapy and vascular invasion were independently associated with DOC with tumour on multivariate analysis (p < 0.05 for all). DOC > or = 2.5 cm was an adverse prognostic factor in univariate analysis (p = 0.002) with a hazard ratio of 1.52 [95% CI 1.13-2.04] compared with those <2.5 cm. Circumferential tumours had a similar prognosis to tumours > or = 2.5 cm (p = 0.60). The prognostic significance of DOC with tumour was lost in multivariate analysis where the factors retaining independence were patient age, T-stage, lymph node metastasis, vascular invasion and positive resection margins. However, when patients were stratified by use of neoadjuvant chemotherapy (n = 121), the DOC with tumour retained prognostic significance on multivariate analysis in the 199 patients who did not undergo neoadjuvant chemotherapy (p = 0.04). CONCLUSION: The DOC with tumour appears to provide prognostic information in oesophageal cancer surgery, especially in patients who do not undergo preoperative chemotherapy.

Emerging aspects of oesophageal and gastro-oesophageal junction cancer histopathology - an update for the surgical oncologist.

Adenocarcinoma of the oesophagus and gastro-oesophageal junction are rapidly increasing in incidence and have a well described sequence of carcinogenesis: the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. During recent years there have been changes in the knowledge surrounding disease progression, cancer management and histopathology specimen reporting. Tumours around the gastro-oesophageal junction (GOJ) pose several specific challenges. Numerous difficulties arise when the existing TNM staging systems for gastric and oesophageal cancers are applied to GOJ tumours. The issues facing the current TNM staging and GOJ tumour classification systems are reviewed in this article. Recent evidence regarding the importance of several histopathologically derived prognostic factors, such as circumferential resection margin status and lymph node metastases, have implications for specimen reporting. With the rising use of multimodal treatments for oesophageal cancer it is important that the response of the tumour to this therapy is carefully documented pathologically. In addition, several controversial and novel areas such as endoscopic mucosal resection, lymph node micrometastases and the sentinel node concept are being studied. We aim to review these aspects, with special relevance to oesophageal and gastro-oesophageal cancer specimen reporting, to update the surgical oncologist with an interest in upper gastrointestinal cancer.

Tumor length as a prognostic factor in esophageal malignancy: univariate and multivariate survival analyses.

BACKGROUND AND OBJECTIVES: Gastrointestinal specialists generally feel that long esophageal tumors carry a worse prognosis and are likely to be more advanced than shorter lesions. Our aim was to investigate the relationship between histologically determined tumor length and aspects of tumor pathology and survival for patients with resected esophageal malignancy. METHODS: Three hundred and nine patients who underwent esophageal resection with curative intent in our unit between 1994 and 2003 were retrospectively analyzed. Pathological details such as TNM stage, differentiation, completeness of surgical resection, and overall stage were collected. Survival data were obtained for each patient and univariate and multivariate analyses were performed. Overall survival was used as the primary endpoint. RESULTS: There were 225 adenocarcinomas, 72 squamous cell carcinomas, and 12 other tumor types with a median tumor length of 3.5 cm (range 0.5-14 cm). Tumor length greater than 3.5 cm was associated with increasing T stage (P = 0.0001), N stage (P = 0.032), overall stage (P = 0.003), and involvement of the longitudinal resection margins (P = 0.02). Univariate analysis found tumor length greater than 3.5 cm was associated with worse overall survival compared with shorter tumors (P = 0.0002). Tumor length remained a significant prognostic factor on multivariate analysis (P = 0.04). Other prognostic factors on multivariate analysis were age, tumor differentiation, nodal involvement, and resection margin status. CONCLUSION: Tumor length greater than 3.5 cm (as determined histologically) is associated with worse disease stage and poor overall patient survival. If preoperative endoscopic tumor length bears a similar relationship, this could assist in patient selection for appropriate treatments.