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Background There is an ongoing need to identify pathologic prognosticators in early-stage oral cavity squamous cell carcinoma (OCSCC) to aid selection of patients who may benefit from adjuvant treatment. The objective of this study was to evaluate the prognostic ability of worst pattern of invasion 5 (WPOI-5) defined by the presence of satellite nodules, extratumoural perineural invasion (PNI) and/or extratumoural lymphovascular space invasion (LVI) in low-stage, node negative OCSCC. Methods Retrospective study of 160 patients with T1/T2N0 tumours staged using TNM7 treated surgically. Histologyof the primary tumour was re-reviewed as appropriate to assess for the presence of WPOI-5 parameters. Univariate and multivariate analysis assessing impact of pathological features on survival outcomes was performed Results On univariate analysis WPOI-5 and it’s 3 constituent components of satellite nodules, extratumoural PNI and extratumoural LVI were all significantly associated with disease-specific survival (DSS) and overall survival (OS). On multivariate analysis satellite nodules (odds ratio, 3.58, 95% CI 1.34, 9.55, p=0.01) and extratumoural LVI (odds ratio 10.94, CI 2.22, 53.79, p=0.003) were independently associated with OS. Postoperative radiotherapy was also significantly associated with OS on multivariate analysis (odds ratio 0.42, CI 0.19, 0.89, p=0.02). Conclusion Satellite nodules and extratumoural LVI correlated significantly with survival outcomes in our early-stage OSCC cohort. Further study is required to investigate the benefit of adjuvant treatment in these cases and to ascertain if worst pattern of invasion-5 parameters should be mandatory reporting data elements.

PDF file - 9585K, Supplementary Figure S3: (A) Representative FOXP3 stained TMA (x1.25). (B) Invasive carcinoma showing absence of FOXP3+ lymphocytes (x20). (C-D) Rare intratumoral FOXP3+ lymphocytes (10) (x20, x40, respectively). (G) Representative T-BET stained TMA (x1.25). (H) Invasive carcinoma showing absence of T-BET+ lymphocytes (x20). (I-J) Rare intratumoral T-BET+ lymphocytes (10) (x20, x40, respectively).

PDF file - 7284K, Supplementary Figure S1: (A) Representative CXCL10 stained TMA (x1.25). (B) Invasive carcinoma showing absence of tumoral CXCL10 expression (x20). (C) Low tumoral CXCL10 expression (x20). (D-E) Moderate and high tumoral CXCL10 expression (x20). (F) Representative CXCR3 stained TMA (x1.25). (G) Invasive carcinoma showing absence of tumoral CXCR3 expression. (H-I) Tumoral CXCR3 expression (x20).

PDF file - 10654K, Supplementary Figure S2: (A) Representative CD4 stained TMA (x1.25). (B) Invasive carcinoma showing absence of intratumoral CD4+ lymphocytes (x20). (C-D) Intratumoral CD4+ lymphocytes (x20, x40, respectively). (E-F) Peritumoral CD4+ lymphocytes (x20, x40, respectively). (G) Representative CD8 stained TMA (x1.25). (H) Invasive carcinoma showing absence of intratumoral CD8+ lymphocytes (x20). (I-J) Rare CD8+ intratumoral lymphocytes (10) (x20, x40, respectively). (M-N) Predominantly peritumoral CD8+ lymphocytes (>10) (x20, x40, respectively).

PDF file - 104K, Table S1. Summary of antibodies and conditions of use Table S2. Pathologic Characteristics of the Breast Tumors Table S3. Association between CXCL10 and CD4 and CD8 peritumoral expression Table S4. (A) Association between FOXP3 and Molecular Biomarkers Table S4. (B) Association between T-BET and Molecular Biomarkers Table S5. (A) Association of FOXP3 and subgroups Table S5. (B) Association of T-BET and subgroups Table S6. (A) Association between FOXP3 and Clinicopathologic parameters Table S6. (B) Association between T-BET and Clinicopathologic parameters

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.

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Supplementary Figure S4: Confirmation of CXCL10 and CXCR3 overexpression in CXCL10-CXCR3 cells. (A) ELISA showing the average level of CXCL10 secreted into the media over 24h by 1x107 CXCL10-CXCR3 or empty vector cells, respectively. (B) Flow cytometry results showing the mean fluorescence intensity of CXCR3 and the percent of CXCR3 positive cells in the CXCL10-CXCR3 and empty vector cell populations, respectively. Filled histograms represent isotype-matched control, and empty histograms represent CXCR3-PE.

Purpose Systematic identification of all 4 parathyroid glands has been recommended during total thyroidectomy (TT); however, it is unclear whether this strategy necessarily translates into optimized functional parathyroid preservation. We wished to investigate the association between number of parathyroids identified intraoperatively during TT, and incidence of incidental parathyroidectomy, and postoperative hypoparathyroidism. Methods Retrospective review of prospectively maintained database of 511 consecutive patients undergoing TT at an academic teaching hospital. The association between number of parathyroid glands identified intraoperatively and incidence of biochemical hypocalcaemia (defined as any calcium n first 48 h after surgery), symptomatic hypocalcaemia; permanent hypoparathyroidism (defined as any hypocalcaemia or need for calcium or vitamin D > 6 months after surgery), and incidental parathyroidectomy, was investigated. The association between number of parathyroid glands visualized and postoperative parathyroid hormone (PTH) levels was investigated in a subset of 454 patients. Results Patients in whom a greater number of parathyroids had been identified had a significantly higher incidence of biochemical and symptomatic hypocalcaemia, and significantly lower postoperative PTH levels, than patients with fewer glands identified. There were no significant differences in incidence of permanent hypoparathyroidism or incidental parathyroidectomy. On multivariate analysis, malignancy, Graves disease, and identification of 3–4 parathyroids were independent predictors of biochemical hypocalcaemia. For symptomatic hypocalcaemia, identification of 2–4 parathyroids, and identification of 3–4 parathyroids, were significant. Conclusions Systematic identification of as many parathyroid glands as possible during TT is not necessary for functional parathyroid preservation.

The precise etiopathogenesis of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and reasons for predilection for crypt epithelium, remain uncertain. The purpose of this study is to investigate the interaction between HPV and specific cytokeratins 7 (CK7) and 19 (CK19) in crypt epithelium. This is a retrospective cohort study of patients presenting between 1999 and 2015 at a tertiary referral center. CK7 and CK19 positivity and H Scores were determined by immunohistochemistry. Disease-specific and overall survival rates were analyzed. There were 253 patients presenting with OPSCC (134), squamous cell carcinoma (SCC) of unknown primary site (22), and oral tongue SCC (97). Primary tumor CK7 and CK19 positivity and H Scores were significantly higher in HPV-positive OPSCC than HPV-negative OPSCC and oral tongue SCC. Higher CK19 Scores, but not CK7 Scores, were also seen in regional metastases from HPV-positive OPSCC than other sites. No impact on disease-specific or overall survival was identified on multivariate analysis. The increased expression of CK7 and CK19 in HPV-positive OPSCC compared to HPV-negative disease supports the theory for a role for these cytokeratins in the etiopathogenesis of HPV-related OPSCC.

Pathological margin assessment is an essential component of surgical management of oral cavity squamous cell carcinoma (OCSCC), however, in many studies, variable definitions of involved margins have been used. The purpose of the present study was to compare the prognostic ability of involved margins according to Royal College of Pathologists (RCPath) and College of American Pathologists (CAP) guidance.Retrospective study of 300 patients with previously untreated OCSCC undergoing definitive surgical management. Main specimen margin status was defined according to RCPath guidance and CAP guidance. "Final margin status", incorporated the results of frozen sections and extra tumour bed resections. The prognostic impact of each margin definition was studied using univariate analysis, and in multivariate models including T-stage (AJCC 8th edition), nodal status (pN+), extranodal extension (ENE), and use of adjuvant radiotherapy.Both RCPath and CAP positive margins were associated with local recurrence (LR), disease-specific survival (DSS), and overall survival (OS) on univariate analysis, while final margin status was associated with LR and DSS, but not OS. On multivariate analysis, only CAP positive main specimen margin status was independently associated with LR (odds ratio 2.44, 95% CI 1.37, 4.34), DSS (odds ratio 2.28, 95% CI 1.31, 3.82), and OS (odds ratio 1.59, 95% CI 1.04, 2.42).Involved main specimen margin as defined by CAP guidance has the advantage of being an independent prognosticator of LR and survival in our cohort.

Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCC) tend to have good outcomes, however a subset does not share this favourable prognosis. The aim of this paper is to investigate the utility of tumour cell anaplasia and multinucleation as prognostic markers in oropharyngeal squamous cell carcinoma. Retrospective review of 104 patients with OPSCC or squamous cell carcinoma of unknown primary site (SCCUP) who underwent primary resection and/or lymph node dissection. Slides of both primary and nodal metastatic disease were assessed for the presence of anaplasia and multinucleation. 53 patients were HPV-positive. Anaplasia was more frequent in males (p = 0.005), smokers (p = 0.003), and HPV-negative disease (p = 0.04). HPV status and > 10 pack-year smoking history were independent predictors of recurrence-free survival (RFS) and disease-specific survival (DSS). Neither anaplasia, nor multinucleation, at the primary site or in cervical metastases, had any significant impact on RFS or DSS. We did not find either anaplasia or multinucleation to have any significant prognostic impact in OPSCC. However, given the small number of adverse events in the HPV-positive cohort, we may have lacked sufficient power to detect significance in what was the subgroup of primary interest. Our study highlights the challenge of identifying markers of poor prognosis in HPV-positive OPSCC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12105-019-01081-7) contains supplementary material, which is available to authorized users.

The precise etiopathogenesis of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and reasons for predilection for crypt epithelium, remain uncertain. The purpose of this study is to investigate the interaction between HPV and specific cytokeratins 7 (CK7) and 19 (CK19) in crypt epithelium.This is a retrospective cohort study of patients presenting between 1999 and 2015 at a tertiary referral center. CK7 and CK19 positivity and H Scores were determined by immunohistochemistry. Disease-specific and overall survival rates were analyzed.There were 253 patients presenting with OPSCC (134), squamous cell carcinoma (SCC) of unknown primary site (22), and oral tongue SCC (97). Primary tumor CK7 and CK19 positivity and H Scores were significantly higher in HPV-positive OPSCC than HPV-negative OPSCC and oral tongue SCC. Higher CK19 Scores, but not CK7 Scores, were also seen in regional metastases from HPV-positive OPSCC than other sites. No impact on disease-specific or overall survival was identified on multivariate analysis.The increased expression of CK7 and CK19 in HPV-positive OPSCC compared to HPV-negative disease supports the theory for a role for these cytokeratins in the etiopathogenesis of HPV-related OPSCC.

Background We aimed to compare the predictive performance of pN-categories in oral squamous cell carcinoma (OSCC) encompassing the most recent 8th edition (TNM8), its predecessor (TNM7), and a newly proposed algorithm (pN-N+), which classifies patients according to the number of positive lymph nodes and extranodal extension. Methods Consecutive, primary OSCC patients from seven previously published cohorts were included and classified according to the three pN-classifications: TNM7, TNM8 and pN-N+. Overall survival probabilities were summarised with the Kaplan–Meier method. We added each of the three metrics to a Cox regression adjusted for pT-category, lymph nodal yield, age, sex, radiotherapy and chemotherapy, and trained these models in one institution. We evaluated the predictive performance in the remaining six institutions and assessed the predicted 5-year risk of death using the area under the receiver operating characteristics curve (AUC) and Brier scores. Results All 1,905 included patients were classified according to TNM7 and pN-N+. A subset of 1,575 patients was additionally classified according to TNM8, leading to upstaging in 27.0%. The pN-N+ ranked overall best determined by the obtained AUC and Brier scores. In contrast to pN-N+, TNM7 and TNM8 both suffered from disproportionate patient distribution across pN-categories and poor pN-categorial discrimination on overall survival. Conclusions The TNM8 pN-classification designates a larger subset to more advanced disease stages but failed to show improvement of its predictive performance compared to TNM7. The pN-categories of TNM7/8 are disproportionate and inconsistently discriminated. The pN-N+ conveyed the best measures of prognosis and should be considered in future TNM iterations.

Background: Two major changes to the staging of oral cavity squamous cell carcinoma (OCSCC) were adopted in TNM8: (1) depth of invasion is now used for T staging and (2) extranodal extension for N staging. The aim of this study was to evaluate if TNM8 stratifies OCSCC patients more accurately than TNM7 based on overall survival (OS) statistics and hazard discrimination. Methods: Retrospective study of 297 patients with OCSCC who underwent surgery at our institution. Clinical and pathological data were previously populated from review of medical charts and histological reports. Slides were re-reviewed for depth of invasion measurements. Patients were staged using both TNM7 and TNM8 with overall survival statistics analysed. Results: Overall 118 patients (39.7%) were upstaged using TNM8. Both TNM7 and TNM8 stage categories were highly significant for OS (all p values < 0.0001). Hazard discrimination analysis showed that TNM7 could only differentiate stage III from stage IV disease with significance (OS p = 0.01). In comparison TNM8 could distinguish between stage II and III disease (OS p = 0.047) and between stage III and IV disease (OS p = 0.004). Subsite analysis suggested that both editions of the staging system perform best for tongue primaries. Conclusions: Although TNM8 showed improved hazard discrimination in comparison to TNM7, problems with discriminative ability persisted with 8th edition staging criteria. Large scale validation studies will be required to direct future refinement of the staging rules and to establish if the continued use of a single staging system for all oral cavity subsites is appropriate.

BACKROUND: The purpose of this study is to assess the impact of trimodal therapy [surgery, chemotherapy and external beam radiotherapy (EBRT)] in patients with anaplastic thyroid cancer (ATC) treated with curative intent. MATERIALS AND METHODS: Retrospective review of patients with ATC treated at a tertiary referral centre between January 2009 and June 2020. Data were collected regarding demographics, histology, staging, treatment and outcomes. RESULTS: Seven patients (4 female) were identified. Median age was 58 years (range 52–83 years). All patients received EBRT with concurrent doxorubicin. Six patients received surgery followed by chemoradiotherapy (CRT), and one underwent neoadjuvant CRT followed by surgery. Median radiological tumour size was 50mm (range 40–90 mm). Six patients had gross extrathyroidal extension and three had N1b disease. Prescribed radiotherapy schedules were 46.4 Gy in 29 bidaily fractions (n = 2, treated 2010), 60 Gy in 30 daily fractions (n = 2), 66Gy in 30 fractions (n = 2) and 70 Gy in 35 fractions (n = 1; patient received neoadjuvant CRT). CRT was discontinued early for two patients due to toxicities. At median follow up of 5.8 months, 42.9% (3/7) patients were alive and disease-free. Only one patient developed a local failure. Three patients died from distant metastases without locoregional recurrence. CONCLUSIONS: Despite poor prognosis of ATC, selected patients with operable tumours may achieve high locoregional control rates with trimodal therapy, with possibility of long-term survival in select cases.

OBJECTIVES: There is no consensus on the optimal approach to human papilloma virus (HPV) testing in oropharyngeal squamous cell carcinoma (OPSCC). Our objective was to classify OPSCC as HPV positive or negative based on (1) morphology alone, (2) p16 status alone, (3) combined morphology and p16 status with additional HPV testing in discordant cases in keeping with 2012 College of American Pathologists (CAP) guidelines (combined approach), and to evaluate and compare survival outcomes.MATERIALS AND METHODS: Retrospective review of 168 patients, 146 with OPSCC and 22 with cervical SCC of unknown primary site (SCCUP). Morphology was classified as keratinizing or non-keratinizing, p16 immunohistochemistry (IHC) performed and additional HPV DNA PCR testing undertaken in cases in which morphology and p16 status were discordant. Survival statistics were evaluated and compared for the 3 different approaches to classification.RESULTS: On univariate analysis all 3 classification methods significantly predicted for overall survival (OS). Both p16 status and the combined approach also predicted for disease specific survival (DSS), whereas morphology fell just outside significance (p = 0.06). On multivariate analysis only the combined approach retained significance for both OS and DSS, whilst morphology was also significant for DSS.CONCLUSIONS: Our findings confirm that tumour morphology significantly predicts for survival in OPSCC. However, we found combined tumour morphology and p16 IHC, with additional testing for discordant cases to be superior to either morphology or p16 IHC alone. Further study is required to establish the optimal testing method for HPV in OPSCC particularly in low prevalence populations.

Background 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). Methods We performed a retrospective review of 55 patients with oropharyngeal SCC undergoing primary surgical treatment. The impact of margin status on disease-specific survival (DSS) was studied according to p16 status. Results Twenty-one patients had positive margins. Adjuvant treatment in these cases was CRT (n = 6), RT alone (n = 14), and none (n = 1). Among p16-negative patients, positive margins and dysplasia at margins predicted significantly worse DSS. Among patients with p16-positive disease, margin status had no impact on DSS. Conclusion Patients with p16-positive oropharyngeal SCC and positive margins after excision maintain a low risk of recurrence despite most receiving RT alone as adjuvant treatment. These findings raise questions regarding the additional benefit of postoperative CRT in this group.

AimsThe assessment of B-raf proto-oncogene, serine/threonine kinase (BRAF) gene status is now standard practice in patients diagnosed with metastatic melanoma with its presence predicting a clinical response to treatment with BRAF inhibitors. The gold standard in determining BRAF status is currently by DNA-based methods. More recently, a BRAF V600E antibody has been developed. We aim to investigate whether immunohistochemical detection of BRAF mutation is a suitable alternative to molecular testing by polymerase chain reaction (PCR).MethodsWe assessed the incidence of BRAF mutation in our cohort of 132 patients, as determined by PCR, as well as examining clinical and histopathological features. We investigated the sensitivity and specificity of the anti-BRAF V600E VE1 clone antibody in detecting the presence of the BRAF V600E mutation in 122 cases deemed suitable for testing.ResultsThe incidence of BRAF mutation in our cohort was 28.8% (38/132). Patients with the BRAF mutation were found to be significantly younger at age of diagnosis. BRAF-mutated melanomas tended to be thinner and more mitotically active. The antibody showed a sensitivity of 86.1% with a specificity of 96.9%. The positive predictive value was 96.9%; the negative predictive value was 94.4%. The concordance rate between PCR and immunohistochemical BRAF status was 95.1% (116/122).ConclusionsThe rate of BRAF mutation in our cohort (28.8%) was lower than international published rates of 40%–60%. This may reflect ethnic or geographic differences within population cohorts. The high concordance rate of PCR and immunohistochemical methods in determining BRAF status suggests that immunohistochemistry is potentially a viable, cost-effective alternative to PCR testing and suitable as a screening test for the BRAF mutation.

Follicular variant papillary thyroid carcinoma (FVPTC) may pose a diagnostic challenge due to higher likelihood of lower risk cytology compared to conventional papillary thyroid carcinoma (CPTC). Recent guidelines have recommended the use of sonographic features to guide decisions to biopsy thyroid nodules. The purpose of this study was to evaluate the sonographic features of CPTC and FVPTC. This is a retrospective study design done in an Academic teaching hospital setting. Preoperative ultrasounds of 79 patients with conventional CPTC (48) and FVPTC (31) were reviewed by a radiologist blinded to histological diagnosis. Sonographic features of nodules were classified according to the British Thyroid Association (BTA) U-classification system as normal (U1), benign (U2), indeterminate (U3), suspicious (U4), and malignant (U5). Pathology slides of patients with FVPTC were reviewed by two pathologists and subclassified into encapsulated, well circumscribed/partly encapsulated, and infiltrative subtypes. FVPTC had a significantly lower incidence of any calcifications (p = 0.0005), microcalcifications (p = 0.002), and irregular or lobulated margins (p = 0.03) than CPTC. Differences in hypoechogenicity (p = 0.06), taller > wide shape (p = 0.17) and presence of halo (p = 0.07) were not significant. FVPTC was significantly less likely to be classified sonographically as malignant (U5) (p = 0.006) or suspicious/malignant (U4/5) (p = 0.009) than conventional PTC. Among FVPTC cases, infiltrative FVPTC were more likely to be sonographically classified as suspicious/malignant (U4/5) than non-infiltrative FVPTC. FVPTC nodules are less likely to show sonographic features of malignancy than conventional PTC. Reliance solely on sonographic features for thyroid nodule evaluation may not be sufficient to exclude FVPTC.

Aims 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. Methods and results Fifty-eight cases of FOM SCC were independently evaluated for the POI and LVI by three pathologists. Interobserver variability was analysed by the use of Fleiss kappa statistics. Interobserver agreement was substantial for the assessment of LVI [κ = 0.64, 95% confidence interval (CI) 0.60–0.68]. Interobserver agreement was moderate for evaluation of the POI with a 50% cut-off (κ = 0.58, 95% CI 0.54–0.62), a 20% cut-off (κ = 0.58, 95% CI 0.54–0.62) cut-off, and worst POI (κ =0 .43, 95% CI 0.39–0.46). A consensus diagnosis of the POI was a significant predictor of locoregional recurrence (LRR), disease-specific survival (DSS) and overall survival (OS) on univariate analysis when a 50% cut-off was used (LRR, P = 0.01; DSS, P = 0.01; OS, P = 0.01) and when a 20% cut-off was used (LRR, P = 0.02; DSS, P = 0.02; OS, P = 0.03), but was not significant when worst POI was used (LRR, P = 0.18; DSS, P = 0.16; OS, P = 0.17). Conclusions Interobserver agreement in the diagnosis of LVI was substantial. The POI at the 50% and 20% cut-offs is moderately reproducible, and has prognostic value in FOM SCC. Further studies are necessary to establish the optimum quantitative cut-off for the POI.

Objectives/Hypothesis 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. Study Design Retrospective study of 96 patients with SCC of the FOM, LA, and RMT undergoing primary surgical treatment. Methods Original pathology reports and slides were reviewed by three pathologists. Level of bone invasion was categorized as cortical or medullary. Main outcome measures were local control (LC) and overall survival (OS). Results Bone invasion was present in 31 cases (32%). On review of pathology slides, all cases of bone invasion demonstrated medullary involvement. Median follow-up was 36 months for all patients, and 53 months for patients not dying from cancer. Among tumors ≤4 cm, bone invasion was associated with significantly worse LC (P =.04) and OS (P =.0005). Medullary invasion (hazard ratio: 2.2, 95% confidence interval: 1.1-4.4, P =.03), postoperative radiotherapy (hazard ratio: 0.3, 95% confidence interval: 0.1-0.5, P

Resection of the submandibular gland is generally undertaken as an integral component of level I neck dissection for oral cancer. However, it is unclear whether lymph nodes are present within the submandibular gland which may form the basis of lymphatic spread. Our purpose was to investigate the frequency of lymph nodes within the submandibular gland, and the incidence and mechanism of submandibular gland involvement in floor of mouth cancer. Retrospective review of 177 patients with oral cancer undergoing neck dissection. Original pathology slides of floor of mouth cases were re-reviewed by two pathologists to determine frequency of intraglandular lymph nodes, and incidence and mechanism of submandibular gland involvement by cancer. The overall incidence of cervical metastases was 36.4 %, of whom 44 % had level I metastases. Level I metastases were significantly more common in floor of mouth than tongue cancers (p = 0.004). Among 50 patients with floor of mouth cancer undergoing re-review of pathology slides, intraglandular lymph nodes were not found in any of 69 submandibular glands. Submandibular gland involvement by cancer was present in two patients, representing 1 % of all oral cancers, and 4 % FOM cases. Mechanisms of involvement were direct extension, and by an apparent novel mechanism of carcinoma growing along bilateral Wharton's ducts. Despite the high incidence of level I metastasis in floor of mouth, lymphatic metastases to submandibular gland are unlikely based on absence of intraglandular lymph nodes. We describe a previously unreported mechanism of submandibular gland involvement.

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.

Background 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. Methods We conducted a retrospective study of 54 consecutive patients undergoing surgery for FOM SCC. Pathological parameters were extracted from histological reports with original pathology slides re-reviewed by 2 pathologists for missing data. Results On univariate analysis, depth of invasion >10 mm (p = .009), lymphovascular invasion (LVI; p < .001), noncohesive invasive front (p = .006), perineural invasion (PNI; p = .003), and nodal metastases (p = .02) were significant predictors of overall survival. On multivariate analysis, LVI (p = .009) and invasive front (p < .001) remained significant. Postoperative radiotherapy improved survival in patients with LVI, PNI, and nodal metastases, and was just outside significance for noncohesive invasive front (p = .06). Conclusion LVI is an adverse prognosticator in FOM SCC and indicates postoperative radiotherapy. Further study is required to investigate the importance of invasive front. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Fibroadenomas (FA) are the most common benign tumor in the female breast. Most are managed conservatively provided there is clinical, radiologic, and pathologic concordance. However, surgical excision is typically recommended for cellular fibroepithelial lesions or those lesions with clinical, radiologic, or pathologic features concerning for phyllodes tumor (PT). Some studies have suggested surgical excision in all FA >30 mm to reduce core needle biopsy (CNB) sampling errors. The aim of our study was to evaluate, in the absence of any other concerning clinicopathologic features, whether surgical excision of FA was warranted based on size criteria alone. Cork University Hospital is a large academic center in Southern Ireland. Its breast cancer center provides both a screening and symptomatic service and diagnoses approximately 600 cancers per year. The breast histopathological data base was reviewed for all CNBs from January 1, 2010, to June 30, 2015, with a diagnosis of FA that went on to have excision at our institution. We excluded all cellular fibroepithelial lesions and those cases with co-existent lobular neoplasia, ductal carcinoma in situ, invasive carcinoma, atypical ductal hyperplasia, or lesions which would require excision in their own right. Cases in which the radiologic targeted mass was discordant with a diagnosis of FA were also excluded. Patient demographics and preoperative radiologic size and the radiologic target were recorded in each case. All radiology was reviewed by a breast radiologist prior to inclusion in the study, and there was histologic radiologic concordance with a diagnosis of FA in all cases. A total of 12,109 consecutive radiologically guided CNB were performed January 2010-June 2015; 3438 with a diagnosis of FA were identified of which 290 cases went on to have surgical excision. Of those 290 cases; 98.28% (n = 285) were confirmed as FA on excision. The remaining 1.72% (n = 5) had atypical features-FA with LCIS (n = 1), benign PT (n = 3), and invasive ductal carcinoma (n = 1). Our study suggests that, excision based solely on size is not warranted in clinical and radiologically concordant cases with a diagnosis of FA on CNB.

Penetrating sea urchin spine injuries, can lead to devastating, irreversible consequences. Persistent inflammation, cutaneous granuloma, neuroma, tenosynovitis, arthritis and destructive arthritis, leading to permanent loss of function and digit amputation, can occur. We present a case of a patient who developed sea urchin spine arthritis of the proximal interphalangeal joint. Only 17 cases of sea urchin spine arthritis of the hand have been documented in the medical literature. However, in this case, the article also includes sequential radiographs, histopathological slides, and intra-operative photographs.

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.

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).We performed a retrospective review of 55 patients with oropharyngeal SCC undergoing primary surgical treatment. The impact of margin status on disease-specific survival (DSS) was studied according to p16 status.Twenty-one patients had positive margins. Adjuvant treatment in these cases was CRT (n = 6), RT alone (n = 14), and none (n = 1). Among p16-negative patients, positive margins and dysplasia at margins predicted significantly worse DSS. Among patients with p16-positive disease, margin status had no impact on DSS.Patients with p16-positive oropharyngeal SCC and positive margins after excision maintain a low risk of recurrence despite most receiving RT alone as adjuvant treatment. These findings raise questions regarding the additional benefit of postoperative CRT in this group.

Objectives: The purpose of this study was to determine the optimum number of cells that should be counted when scoring human epidermal growth factor receptor 2 (HER2) brightfield dual-color in situ hybridization (BDISH), including cases with HER2 /chromosome 17 (Chr17) ratios in the 1.80 to 2.20 range. Methods: In total, 131 cases of breast carcinoma with HER2 immunohistochemistry and BDISH were included. For cases with a HER2 /Chr17 ratio of less than 1.80 or more than 2.20 (n = 115), BDISH scoring was performed for 60 cells using three tumor fields, and for cases with a HER2 /Chr17 ratio of 1.80 to 2.20 (n = 16), scoring was performed for 120 cells using six tumor fields. Mean HER2 /Chr17 ratio and HER2 copy number were calculated for cumulative cell counts. Results: The HER2 status as determined by the HER2 /Chr17 ratio or HER2 copy number was unchanged following counting of additional cells in 100% of cases with ratio of less than 1.80 or more than 2.20. The HER2 status of two cases with ratios of 1.80 to 2.20 changed from positive to negative following counting of 120 cells. Conclusions: Our findings support recommendations to score 20 nuclei in conjunction with careful assessment of immunohistochemistry and scan of the BDISH slide to identify areas of heterogeneity. Scoring of additional cells/fields is likely not of benefit and might be a disadvantage since the scorer moves out of the area of strongest signal.

IntroductionFine needle aspiration cytology (FNAC) of radiologically abnormal axillary lymph nodes in patients with breast cancer can identify patients suitable for primary axillary clearance (AC) rather than sentinel node biopsy, enabling surgical axillary staging by a single operation. This study assessed the accuracy of FNAC in predicting positive axillary lymph nodes.Methods161 patients with screen-detected invasive carcinoma and who had pre-operative FNAC of a radiologically abnormal axillary lymph node were identified from two screening units, The axillary FNAC reports were correlated with sentinel node biopsy and AC reports, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated.ResultsFNAC had a moderate sensitivity (66.3%) and NPV (71.8%), and a high specificity (98.7%) and PPV (98.3%). Most patients (86%) had a single axillary operation. The sensitivity was highest in grade 3 (81.8%) and ductal type (77.8%) tumours. The sensitivity was lower in tumours of special type (34.8%), grade 1 tumours (50%) and those without lymphovascular invasion (LVI) (55.9%). The NPV was highest in pT1 (86.7%) and in grade 1 (84.5%) tumours, and lowest (44%) in tumours with LVI. The PPV was 100% in grade 1 and 3 tumours, stage pT2 and pT3 tumours and those without LVI, and was high (>96%) in all other groups. In lymph-node-positive patients, the mean number of lymph nodes involved was higher in the case of a positive (6.4) than negative FNAC (4.4).ConclusionsFNAC of ultrasonically abnormal axillary lymph nodes achieved surgical staging by a single operation in most patients with screen-detected invasive breast carcinoma, with moderate sensitivity and high specificity.

AimsMost studies comparing full-field digital mammography (FFDM) with conventional screen-film mammography (SFM) have been radiology-based. The pathological implications of FFDM have received little attention in the literature, especially in the context of screening programmes. The primary objective of this retrospective study is to compare FFDM with SFM in a population-based screening programme with regard to a number of pathological parameters.MethodsDuring the study period, 107 818 women underwent screening mammograms with almost equal numbers obtained with each technique (49.9% with SFM vs 50.1% with FFDM). We compared SFM with FFDM using the following parameters: recall rate, diagnostic core biopsy rate, cancer detection rates, B3 rate, B4 rate, preoperative diagnostic rate for malignancy, positive predictive values and tumour characteristics.ResultsThe recall rate was significantly higher with FFDM (4.21% vs 3.52%, pConclusionsThe higher cancer detection rate with FFDM in this study was due to improved detection of microcalcifications. However, this was achieved at the cost of a higher recall rate and a higher B3 rate, indicating that overtreatment may be problematic with digital mammography.

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.Retrospective study of 96 patients with SCC of the FOM, LA, and RMT undergoing primary surgical treatment.Original pathology reports and slides were reviewed by three pathologists. Level of bone invasion was categorized as cortical or medullary. Main outcome measures were local control (LC) and overall survival (OS).Bone invasion was present in 31 cases (32%). On review of pathology slides, all cases of bone invasion demonstrated medullary involvement. Median follow-up was 36 months for all patients, and 53 months for patients not dying from cancer. Among tumors ≤4 cm, bone invasion was associated with significantly worse LC (P =.04) and OS (P =.0005). Medullary invasion (hazard ratio: 2.2, 95% confidence interval: 1.1-4.4, P =.03), postoperative radiotherapy (hazard ratio: 0.3, 95% confidence interval: 0.1-0.5, P.001), and positive pathologic nodal status (hazard ratio: 4.1, 95% confidence interval: 1.9-8.6, P.001) were independent predictors of worse OS among the entire cohort.Mandibular medullary bone invasion is a poor prognosticator in oral cancers, irrespective of small size of primary tumor. Such cases should be considered for postoperative radiotherapy.4. Laryngoscope, 127:849-854, 2017.

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.We conducted a retrospective study of 54 consecutive patients undergoing surgery for FOM SCC. Pathological parameters were extracted from histological reports with original pathology slides re-reviewed by 2 pathologists for missing data.On univariate analysis, depth of invasion10 mm (p = .009), lymphovascular invasion (LVI; p.001), noncohesive invasive front (p = .006), perineural invasion (PNI; p = .003), and nodal metastases (p = .02) were significant predictors of overall survival. On multivariate analysis, LVI (p = .009) and invasive front (p.001) remained significant. Postoperative radiotherapy improved survival in patients with LVI, PNI, and nodal metastases, and was just outside significance for noncohesive invasive front (p = .06).LVI is an adverse prognosticator in FOM SCC and indicates postoperative radiotherapy. Further study is required to investigate the importance of invasive front. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1528-E1534, 2016.

Importance The follicular variant (FV) of papillary thyroid carcinoma (PTC) is an important subtype that can be difficult to diagnose using preoperative cytologic analysis. Objective To compare conventional and FV PTC with regard to preoperative cytologic diagnosis using a tiered thyroid cytologic reporting system, tumor size at diagnosis, presence of invasion, and implications on prognostic scores. Design, Setting, and Participants This retrospective study was conducted in an academic teaching hospital and included 99 patients with conventional (n = 65) or FV (n = 34) PTC. Interventions Preoperative thyroid cytologic findings, originally reported using the tiered British Thy system, were recategorized according to the Bethesda classification system. Pathologic features recorded included tumor size, presence of extrathyroid extension (ETE), and metastases. Prognostic scores were calculated according to the MACIS system. Main Outcomes and Measures Differences in patient demographics, preoperative cytologic findings, tumor pathologic features, and prognostic risk categories between conventional and FV PTC were studied. Results There were no differences in patient age or sex. Cytologic findings from FV PTC were significantly more likely to be reported in a lower-risk category than those from conventional PTC for (1) malignant vs lower-risk category (22 [56%] vs 2 [8%]); (2) suspected malignant or malignant vs lower-risk category (26 [66%] vs 6 [23%]); and (3) follicular neoplasm or higher-risk category vs lower-risk category (34 [87%] vs 10 [38%]) ( P P = .03). The mean size of FV PTC lesions (25.9 mm) at the time of pathologic diagnosis was significantly greater than that of conventional PTC lesions (15.5 mm) ( P = .02). Even after exclusion of “coincidental” carcinomas, FV PTC tumors were significantly larger than conventional PTC tumors (31.7 vs 22.4 mm; P = .03). In contrast, FV PTC was significantly less likely to show ETE (0 of 34 vs 10 of 65; P = .01). There were no significant differences between FV PTC and conventional PTC in proportion of patients in intermediate- and high-risk prognostic groups combined (21 [62%] vs 38 [58%]) ( P = .83) or in mean MACIS scores (4.68 and 4.38, respectively; P = .18). Conclusions and Relevance Preoperative cytologic findings from FV PTC were more likely than those from conventional PTC to indicate a lower risk category, and FV PTC tumors were larger at time of diagnosis. On the other hand, owing to a lower incidence of ETE in conventional PTC, there was no difference in prognostic score at diagnosis.

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.

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 (

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.