Linda Feeley

Tumoral Lymphocytic Infiltration and Expression of the Chemokine CXCL10 in Breast Cancers from the Ontario Familial Breast Cancer Registry

Purpose: Breast carcinomas, including basal and hereditary cases, often present with a prominent tumoral lymphocytic infiltrate. Chemokines could play a role in attracting these cells and contribute to tumor progression. We explored tumoral expression of CXCL10 and determined the relationship between CXCL10 and lymphocytic infiltrate in a cohort of breast cancers. Experimental Design: Using tissue microarrays of 364 breast tumors, we evaluated expression of CXCL10 and its receptor, CXCR3, in relation to histopathologic features, biomarkers, and lymphocyte markers. In addition, we overexpressed CXCL10 and CXCR3 in MCF7 breast cancer cells and monitored T-lymphocyte migration and invasion. Results: Forty-five percent of tumors expressed CXCL10, and a significant association was found with CXCR3 and lymphocytic infiltrate. Further characterization of the lymphocytic infiltrate revealed an association with CXCL10 expression for peritumoral CD4+ and CD8+ lymphocytes. CD8+ intratumoral lymphocytes, FOXP3+ regulatory T cells (Tregs), and T-BET+ TH1 cells were associated with BRCA1 and basal tumors. Conditioned media from MCF7 cells overexpressing both CXCL10 and CXCR3 increased T-lymphocyte migration and invasion. Conclusions: Our findings suggest that CXCL10 may act in a paracrine manner, affecting the tumor microenvironment, and in an autocrine manner, acting on the tumor cells themselves and may play a role in tumor invasiveness and progression. The CXCL10-CXCR3 axis can serve as a potential target in BRCA1 and basal breast cancers, which present with a prominent lymphocytic infiltrate and a poor prognosis. Clin Cancer Res; 19(2); 336–46. ©2012 AACR.

Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information

The objectives of this study were to determine the prognostic significance of subgrouping estrogen receptor (ER)-positive breast tumors into low- and high-risk luminal categories using Ki67 index, TP53, or progesterone receptor (PR) status. The study group comprised 540 patients with lymph node negative, invasive breast carcinoma. Luminal A subtype was defined as being ER positive, HER2 negative, and Ki67 low (<14% cells positive) and luminal B subtype as being ER positive, HER2 negative, and Ki67 high (≥14% cells positive). Luminal tumors were also subgrouped into risk categories based on the PR and TP53 status. Survival analysis was performed. Patients with luminal B tumors (n=173) had significantly worse disease-free survival compared to those with luminal A tumors (n=186) (log rank P-value=0.0164; univariate Cox regression relative risk 2.00; 95% CI, 1.12–3.58; P=0.0187). Luminal subtype remained an independent prognostic indicator on multivariate analysis including traditional prognostic factors (relative risk 2.12; 95% CI, 1.16–3.88; P=0.0151). Using TP53 status or PR negativity rather than Ki67 to classify ER-positive luminal tumors gave similar outcome results to those obtained using the proliferation index. However, it was a combination of the three markers, which proved the most powerful prognostically. Ki67 index, TP53 status, or PR negativity can be used to segregate ER-positive, HER2-negative tumors into prognostically meaningful subgroups with significantly different clinical outcomes. These biomarkers particularly in combination may potentially be used clinically to guide patient management.

Sentinel lymph node biopsy is not warranted following a core needle biopsy diagnosis of ductal carcinoma in situ (DCIS) of the breast

INTRODUCTION The role of sentinel lymph node biopsy (SLNB) in ductal carcinoma in situ (DCIS) is controversial. This study evaluates the risk of clinically relevant SLN metastasis following a core needle biopsy (CNB) diagnosis of pure DCIS. MATERIALS AND METHODS Cases that underwent SLNB following a CNB diagnosis of pure DCIS at our institution over a 4.5 year period were evaluated. Parameters including the DCIS characteristics on CNB, the rate of upstaging to invasive carcinoma at excision and the SLNB result were recorded. RESULTS Of 296 patients with a CNB diagnosis DCIS, 181 had SLNB (62%). The rate of invasion at excision in those undergoing SLNB was 30% (54/181). SLN metastasis was detected in 7/181 cases (4%), including 6 cases with isolated tumour cells only (3.5%) and only 1 case with a macro-metastatic deposit (0.5%). CONCLUSION The risk of clinically significant SLN metastasis following a CNB diagnosis of DCIS is extremely low, despite a relatively high rate of upstaging to invasive carcinoma at excision. Our findings support the opinion that SLNB is not warranted following a CNB diagnosis of DCIS, particularly for those patients undergoing breast conservation surgery.

Impact of positive margins on outcomes of oropharyngeal squamous cell carcinoma according to p16 status

Currently, positive surgical margins in head and neck cancer are considered to be an indicator for postoperative chemoradiotherapy (CRT) over radiotherapy (RT) alone. However, there are less data regarding the impact of margin status on human papillomavirus (HPV)‐related oropharyngeal squamous cell carcinoma (SCC).

Association of Extracapsular Spread With Survival According to Human Papillomavirus Status in Oropharynx Squamous Cell Carcinoma and Carcinoma of Unknown Primary Site

IMPORTANCE The presence of extracapsular spread (ECS) of metastatic nodes is considered a poor prognosticator in head and neck cancer, with postoperative chemoradiation therapy often recommended over radiation therapy alone in such cases. However, there is less clarity regarding the effect of ECS on human papillomavirus-associated oropharynx squamous cell carcinoma (OPSCC) or carcinoma of unknown primary site (CUP). OBJECTIVE To investigate the association of ECS according to human papillomavirus status in OPSCC and CUP with survival. DESIGN, SETTING, AND PARTICIPANTS This investigation was a retrospective cohort study performed between August 1998 and March 2015 at an academic teaching hospital. Participants were 83 patients with OPSCC (n = 62) or CUP (n = 21) undergoing neck dissection as part of initial treatment. MAIN OUTCOME AND MEASURES Human papillomavirus status was determined by p16 immunohistochemistry. The presence of ECS was extrapolated from pathology reports, and the extent of ECS was determined by rereview of original pathology slides. Disease-specific survival (DSS) and recurrence-free survival (RFS) were assessed. RESULTS Among 83 patients (71 male), there were 45 p16-positive and 38 p16-negative tumors. Fifty-one patients had ECS, which was graded as extensive in 43 cases. The median follow-up was 31 months for all patients and 50 months for surviving patients. Among the entire cohort, adverse predictors of RFS were p16-negative status (hazard ratio [HR], 9.4; 95% CI, 3.3-27.2) and ECS (HR, 6.5; 95% CI, 2.0-21.6). Adverse predictors of DSS were p16-negative status (HR, 16.8; 95% CI, 3.9-71.2) and ECS (HR, 8.3; 95% CI, 2.0-35.3). Among p16-negative patients, ECS was significantly associated with worse RFS (HR, 9.7; 95% CI, 1.3-72.3) and DSS (HR, 8.7; 95% CI, 1.1-62.7). In contrast, among p16-positive patients, ECS had no effect on RFS (HR, 1.1; 95% CI, 0.2-7.8) or DSS (HR, 1.2; 95% CI, 0.1-18.7). CONCLUSIONS AND RELEVANCE The presence of ECS appears to be associated with survival in OPSCC and CUP according to p16 status. Our findings raise questions regarding the benefits of postoperative chemoradiation therapy in p16-positive patients with ECS.

Impact of mandibular invasion on prognosis in oral squamous cell carcinoma four centimeters or less in size

Previous studies have reported variable results for the impact of bone invasion on survival in oral cancer. It is unclear whether bone invasion in small (≤4 cm) squamous cell carcinomas (SCC) of the oral cavity is an independent adverse prognosticator. Our objective was to investigate impact on survival of bone invasion in SCC of floor of mouth (FOM), lower alveolus (LA), and retromolar trigone (RMT) ≤4 cm in size.

Importance of lymphovascular invasion and invasive front on survival in floor of mouth cancer.

The floor of mouth (FOM) is a common site of oral squamous cell carcinoma (SCC). The purpose of this study was to investigate pathological predictors of survival in FOM SCC.

Pattern of invasion and lymphovascular invasion in squamous cell carcinoma of the floor of the mouth: an interobserver variability study.

Lymphovascular invasion (LVI) and the histological pattern of invasion (POI) at the invasive tumour front have been reported as adverse prognosticators in oral squamous cell carcinoma (SCC). However, assessment of these parameters is hampered by variation in the criteria used for their evaluation. Our objective was to evaluate interobserver variability in the assessment of the POI and LVI in SCC of the floor of the mouth (FOM), and to study the impact of the POI on clinical outcomes by using varying quantitative cut‐offs.

When pathological and radiological correlation is achieved, excision of fibroadenoma with lobular neoplasia on core biopsy is not warranted

BACKGROUND The diagnosis and management of lobular neoplasia (LN) including lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH) remains controversial. Current management options after a core needle biopsy (CNB) with lobular neoplasia (LN) incorporating both ALH and LCIS include excision biopsy or careful clinical and radiologic follow up. METHODS A retrospective analysis of the surgical database at Cork University Hospital was performed to identify all core needle biopsies from January 1st 2010 to 31st December 2013 with a diagnosis of FA who subsequently underwent surgical excision biopsy. All cases with associated LN including ALH and classical LCIS were selected. We excluded cases with coexistent ductal carcinoma in situ (DCIS), invasive carcinoma, LN associated with necrosis, pleomorphic lobular carcinoma in situ (PLCIS) or lesions which would require excision in their own right (papilloma, radial scar, atypical ductal hyperplasia (ADH) or flat epithelial atypia (FEA)). Cases in which the radiologic targeted mass was discordant with a diagnosis of FA were also excluded. RESULTS 2878 consecutive CNB with a diagnosis of FA were identified. 25 cases had a diagnosis of concomitant ALH or classical LCIS. Our study cohort consisted of 21 women with a mean age 53 years (age range 41-70 years). The core biopsy diagnosis was of LCIS and FA in 16 cases and ALH and FA in 5 cases. On excision biopsy, a FA was confirmed in all 21 cases. In addition to the FA, residual LCIS was present in 14 cases with residual ALH in 2 cases. One of the twenty-one cases (4.8%) was upgraded to invasive ductal carcinoma on excision.

Reflex Repeat HER2 Testing of Grade 3 Breast Carcinoma at Excision Using Immunohistochemistry and In Situ Analysis: Frequency of HER2 Discordance and Utility of Core Needle Biopsy Parameters to Refine Case Selection.

OBJECTIVES The updated American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines (2013) for human epidermal growth factor receptor 2 (HER2) testing in breast cancer recommend repeat testing at excision of HER2-negative grade 3 breast tumors. This study aimed to identify the rate of HER2 discordance in this cohort of cases. METHODS All HER2-negative grade 3 tumors diagnosed at a single institution over a 15-month period had reflex repeat HER2 testing at excision : HER2 testing was performed in accordance with ASCO/CAP guidelines using immunohistochemistry (IHC) and dual in situ hybridization (ISH). RESULTS One hundred cases were identified over the study period. HER2 was amplified at excision in three cases. The discordant tumors showed equivocal IHC at excision with low-level amplification on dual ISH. All discordant cases showed equivocal IHC on core needle biopsy (CNB) specimens and/or tumor upgrade at excision. CONCLUSIONS Our series demonstrated a high concordance rate (97%) for HER2 at excision in grade 3 breast tumors with a negative core biopsy result. These findings suggest that reflex repeat HER2 testing of all these cases, which has significant cost and workload implications, may not be justified. Features that may indicate HER2 heterogeneity, such as equivocal IHC on CNB specimens or tumor upgrade at excision, may help refine selection of cases for repeat testing.