Using quantitative tissue phenotype to assess the margins of surgical samples from a pan-Canadian surgery study.

BACKGROUND: The purpose of this study was to use quantitative tissue phenotype (QTP) to assess the surgical margins to examine if a fluorescence visualization-guided surgical approach produces a shift in the surgical field by sparing normal tissue while catching high-risk tissue. METHODS: Using our QTP to calculate the degree of nuclear chromatin abnormalities, Nuclear Phenotypic Score (NPS), we analyzed 1290 biopsy specimens taken from surgical samples of 248 patients enrolled in the Efficacy of Optically-guided Surgery in the Management of Early-staged Oral Cancer (COOLS) trial. Multiple margin specimens were collected from each surgical specimen according to the presence of fluorescence visualization alterations and the distance to the surgical margins. RESULTS: The NPS in fluorescence visualization-altered (fluorescence visualization-positive) samples was significantly higher than that in fluorescence visualization-retained (fluorescence visualization-negative) samples. There was a constant trend of decreasing NPS of margin samples from non-adjacent-fluorescence visualization margins to adjacent-fluorescence visualization margins. CONCLUSION: Our results suggested that using fluorescence visualization to guide surgery has the potential to spare more normal tissue at surgical margins.

Primary treatment for oropharyngeal squamous cell carcinoma in Alberta, Canada: A population-based study.

BACKGROUND: The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) is increasing and has better survival than non-HPV related oropharyngeal SCC. This study compared surgical to nonsurgical treatments and demographic, clinical, and survival differences in patients with oropharyngeal SCC, stratified by p16 status. METHODS: We assembled a cohort of adult patients with oropharyngeal SCC diagnosed between 2000 and 2008 in Alberta. The tumor p16 biomarker was measured using fluorescent immunohistochemistry. RESULTS: In this cohort, p16 data were available for 115 of 357 patients; and 66% (n = 76) were p16-positive. Patients with p16 data had comparable outcomes to those without. Surgically treated p16-negative patients had improved 5-year disease-specific survival (DSS) and overall survival (OS) compared with nonsurgical patients. There were no differences in survival outcomes between surgical and nonsurgical treatment for patients with p16-positive disease. CONCLUSION: Patients with p16-positive oropharyngeal SCC had similar outcomes regardless of treatment. Patients with p16-negative tumors may benefit from primary surgery with postoperative adjuvant therapy.

Canadian family physician knowledge and attitudes toward laboratory utilization management.

OBJECTIVES: Mitigation of unnecessary and redundant laboratory testing is an important quality assurance priority for laboratories and represents an opportunity for cost savings in the health care system. Family physicians represent the largest utilizers of laboratory testing by a large margin. Engagement of family physicians is therefore key to any laboratory utilization management initiatives. Despite this, family physicians have been largely excluded from the planning and implementation of such initiatives. Our purposes were to (1) assess the importance of lab management issues to family physicians, and (2) attempt to define the types of initiatives most acceptable to family physicians. DESIGN AND METHODS: We invited all Alberta family practice residents and practicing physicians to participate in a self-administered online electronic survey. Survey questions addressed the perceived importance of lab misutilization, prevalence of various types of misutilization, acceptability of specific approaches to quality control, and responsibility of various parties to address this issue. RESULTS: Of 162 respondents, 95% considered lab misutilization to be either important or very important. Many physicians placed the responsibility for addressing lab misutilization issues on multiple parties, including patients, but most commonly the ordering physician (97%). Acceptability for common strategies for quality improvement in lab misutilization showed a wide range (35%-98%). CONCLUSIONS: These responses could serve as a framework for laboratories to begin discussions on this important topic with primary care groups.

Fractal analysis of nuclear histology integrates tumor and stromal features into a single prognostic factor of the oral cancer microenvironment.

BACKGROUND: The lack of prognostic biomarkers in oral squamous cell carcinoma (OSCC) has hampered treatment decision making and survival in OSCC remains poor. Histopathological features are used for prognostication in OSCC and, although useful for predicting risk, manual assessment of histopathology is subjective and labour intensive. In this study, we propose a method that integrates multiple histopathological features of the tumor microenvironment into a single, digital pathology-based biomarker using nuclear fractal dimension (nFD) analysis. METHODS: One hundred and seven consecutive OSCC patients diagnosed between 1998 and 2006 in Calgary, Canada were included in the study. nFD scores were generated from DAPI-stained images of tissue microarray (TMA) cores. Ki67 protein expression was measured in the tumor using fluorescence immunohistochemistry (IHC) and automated quantitative analysis (AQUA®). Lymphocytic infiltration (LI) was measured in the stroma from haematoxylin-eosin (H&E)-stained TMA slides by a pathologist. RESULTS: Twenty-five (23.4%) and 82 (76.6%) patients were classified as high and low nFD, respectively. nFD was significantly associated with pathological tumor-stage (pT-stage; P = 0.01) and radiation treatment (RT; P = 0.01). High nFD of the total tumor microenvironment (stroma plus tumor) was significantly associated with improved disease-specific survival (DSS; P = 0.002). No association with DSS was observed when nFD of either the tumor or the stroma was measured separately. pT-stage (P = 0.01), pathological node status (pN-status; P = 0.02) and RT (P = 0.03) were also significantly associated with DSS. In multivariate analysis, nFD remained significantly associated with DSS [HR 0.12 (95% CI 0.02-0.89, P = 0.04)] in a model adjusted for pT-stage, pN-status and RT. We also found that high nFD was significantly associated with high tumor proliferation (P < 0.0001) and high LI (P < 0.0001), factors that we and others have shown to be associated with improved survival in OSCC. CONCLUSIONS: We provide evidence that nFD analysis integrates known prognostic factors from the tumor microenvironment, such as proliferation and immune infiltration, into a single digital pathology-based biomarker. Prospective validation of our results could establish nFD as a valuable tool for clinical decision making in OSCC.

Diagnostic utility of central node necrosis in predicting extracapsular spread among oral cavity squamous cell carcinoma.

BACKGROUND: Oral cavity squamous cell carcinoma (SCC) represents the most common SCC affecting the head and neck region. Long-term survival of patients with oral cavity SCC is adversely affected by lymph node metastasis and further decreased by the presence of lymph node extracapsular spread (ECS). METHODS: Using a case-control design, preoperative CT scans from patients with oral cavity SCC and metastatic lymphadenopathy were evaluated by 2 independent neuroradiologists, blinded to the study, for a number of radiologic parameters, including central node necrosis. Multivariate logistic regression was used to identify parameters independently predicting pathologic ECS. RESULTS: For both neuroradiologists, central node necrosis was a significant predictor of ECS, with high interrater agreement (kappa = 0.71). On multivariate analysis, only central node necrosis independently predicted ECS (odds ratio [OR] = 12.1; 95% confidence interval [CI] = 1.24-119). Central node necrosis predicted ECS with 91% sensitivity and 88% negative predictive values. CONCLUSION: Our findings suggest that central node necrosis on preoperative CT scans is strongly associated with the presence of ECS.

Cytopathology including fine-needle aspiration in sub-Saharan Africa: a Cameroon experience.

CONTEXT: Surgical pathology is unavailable in most of sub-Saharan Africa because of equipment costs and lack of expertise. Cytopathology is an inexpensive and reliable alternative. OBJECTIVE: To explore the utility of cytopathology in a rural hospital setting in Africa. DESIGN: A cytopathologist and a pathology resident from Calgary, Alberta, Canada, went to Cameroon to provide a cytopathology service at the Banso Baptist Hospital. Both performed the fine-needle aspiration procedures. Direct smears were fixed in alcohol and stained with hematoxylin-eosin. Surgical specimens subsequently obtained from the patients were processed and reported at Calgary Laboratory Services, Canada. The histopathologic diagnoses were the gold standard for determining the accuracy of the cytologic diagnoses. RESULTS: Fifty-nine patients were examined during a 5-week period, 33 females (56%) and 26 males (44%). Sixteen (27%) were known to be HIV positive. Forty-four fine-needle aspiration procedures were performed for 43 patients (73%). The cost of each procedure was approximately US $10. Head and neck and breast were the sites most frequently sampled for aspirates. Cervical smears from 5 patients were also assessed, as were 8 fluid specimens and 2 touch preparations of prostatic core biopsies. The most frequent diagnoses for malignancy were carcinoma and lymphoma. Tuberculous lymphadenitis was diagnosed in 6 patients, 4 of whom were HIV positive. Surgical specimens were received from 18 patients (30%). Cytohistologic and clinicopathologic correlation revealed 1 false-positive (1.6%) and 1 false-negative (1.6%) diagnosis. CONCLUSION: Cytopathology is a reliable alternative for tissue diagnosis in low-resource settings.

Genomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosis.

AIMS: To compare the expression of genes involved in p53, Wnt/beta-catenin, and retinoblastoma (Rb) 1 pathways between cirrhosis-associated hepatocellular carcinoma (HCC-C) and hepatocellular carcinoma arising in non-cirrhotic liver (HCC-NC). METHODS AND RESULTS: The gene expression profile was analysed using oligo-DNA arrays, and then validated at protein level in a tissue microarray using immunohistochemistry. Compared with their background non-neoplastic liver tissue, HCC-C showed a significantly higher rate of p53, beta-catenin (protein only) and cyclin D1 expression, whereas HCC-NC showed a significantly higher rate of p21(Waf1/cip1) and p27(Kip1) expression. HCC-C had a significantly higher rate of p53 expression and a significantly lower rate of p21(waf1/cip1) expression than HCC-NC. There was no statistically significant association between the expression of genetic markers and tumour histological grade, underlying aetiology, or lymphovascular invasion. Aberrant beta-catenin expression was more commonly seen in single tumours in comparison with multiple tumours. Increased p16(INK4) and p21(waf1/cip1) expression was more commonly observed in large-sized tumours (>50 mm) than small-sized tumours. CONCLUSIONS: Alteration of the p53 pathway plays a more important role in the pathogenesis of HCC-C, whereas alterations in cell cycle regulators p21(waf1/cip1) and p27(Kip1) play a more important role in the pathogenesis of HCC-NC.

Mantle cell lymphoma of the oral cavity: case series and comprehensive review of the literature.

OBJECTIVE: Mantle cell lymphoma (MCL) is a rare B-cell neoplasm that has only recently been defined as a distinct entity. Because of its rarity and histologic similarities to other small cell lymphomas, the microscopic diagnosis of MCL may be challenging. This is particularly true within the oral cavity, where other lymphomas are more frequent. To date, few cases of MCL presenting within the oral cavity have been reported. STUDY DESIGN: We present 2 new cases of MCL within the oral cavity and systematically review 7 other cases of MCL reported in the English-language literature. Historical cases were reviewed, and available data regarding morphology, special stains, demographics, clinical presentation, radiographic findings, management, and outcome were extracted. Data from our present series were then compared with the earlier published literature. RESULTS: To the best of our knowledge, this is the largest reviewed series of MCL within the oral cavity, totaling 9 cases. The features of our cases, including histology, clinical presentation, and outcome, are consistent with the 7 earlier reported cases. The majority of oral MCLs occur in an older male population, and a high proportion occur on the palate. CONCLUSION: We conclude that MCL of the oral cavity is an uncommon diagnosis. Most oral MCLs occur in an elderly male population and have a possible predilection for the palate. The microscopic diagnosis can be challenging, given its similar appearance to other small cell lymphomas, requiring a comprehensive immunohistochemical panel for the accurate diagnosis. Like MCL occurring in other sites in the body, the prognosis and outcome of oral MCL appears to be poor.

Arias-Stella reaction as a diagnostic pitfall in a bladder biopsy with endometriosis: case report and review of the pseudoneoplastic bladder lesions.

Arias-Stella reaction is a hormone-induced atypical endometrial change that may involve endometrial, extraendometrial, or endometriotic sites. Establishing a correct diagnosis of Arias-Stella reaction may sometimes be problematic when seen outside of the uterine corpus, particularly in a limited biopsy sample when the pathologist is not aware of the clinical history. We report an Arias-Stella reaction in bladder endometriosis, which presented as a bladder mass in a 25-year-old pregnant woman. Clinical information of intrauterine pregnancy (week 16) was not initially provided when the biopsy was performed. We also discuss endometriosis, endocervicosis, and müllerianosis of the bladder, which are benign glandular lesions that may mimic tumors within the bladder wall.

A pathologic re-review of follicular thyroid neoplasms: the impact of changing the threshold for the diagnosis of the follicular variant of papillary thyroid carcinoma.

BACKGROUND: Histopathologic criterion for follicular variant of papillary thyroid cancer (FVPTC) has only recently been utilized universally. The purpose was to determine whether, on review, these criteria would result in a change in diagnosis of follicular neoplasm (FN). METHODS: A ten-year clinical cohort included patients with a diagnosis of a follicular adenoma, follicular carcinoma (FC), or FVPTC. The archived sections were re-examined by two pathologists blinded to the original diagnoses. Clinical follow-up, including ultrasonography, was carried out on all patients with a change in diagnosis. RESULTS: One hundred eighty-five patients met the inclusion criteria. Initially, 118 were benign, 56 were FVPTC, and 11 were FC. Overall, 46 (25%) patients had a change in diagnosis on re-review; 35 were reclassified from a benign diagnosis to a re-reviewed malignant diagnosis, with 5 reclassified as minimally invasive FC, 4 as occult PTC, and 26 (74%) as FVPTC. Of the 26 FVPTC, only 10 (38%) had undergone a total thyroidectomy (TT). The mean follow-up was 105 months (range, 24-156). None of these patients had evidence of recurrent or persistent disease. Eleven patients were reclassified to a benign diagnosis. Eight have undergone a TT, with 3 of these patients receiving I(131) ablation therapy. A third independent thyroid pathologist also reviewed the histopathologic slides of these 46 patients and concurred with the change in diagnosis in 41 of the 46 patients. CONCLUSIONS: Reclassification of FN increased malignant lesions from 36% to 48%. Although there have been no clinical ramifications in the patients with a changed diagnosis, the ethical issues surrounding these 46 patients are important and present a substantive quandary to the clinicians responsible for their care.

DNA sequence-based detection of group B Streptococcus directly from heart valve tissue in a patient with culture-negative endocarditis.

A human case of culture-negative bacterial endocarditis is presented where conventional methods failed to determine a microbial aetiology. DNA sequencing performed directly on autopsy heart valve tissue revealed Streptococcus agalactiae (group B streptococcus). To our knowledge, this is the first report of DNA sequence-based detection of this organism directly from a heart valve.

Enterocolic lymphocytic phlebitis: statistical analysis of histology features in viable and ischemic bowel.

Enterocolic lymphocytic phlebitis is a rare cause of segmental ischemic enterocolitis. This artery-sparing transmural vasculitis is classically a circumferential phlebitis with perivenular lymphocyte cuffing and thrombi in the absence of systemic manifestations. Myointimal hyperplasia may represent a chronic phase of enterocolic lymphocytic phlebitis. Subclinical or early stage enterocolic lymphocytic phlebitis is not well delineated. We analyzed 600 submucosal and subserosal veins from both ischemic and intact bowel segments to discern if vascular morphology varied between sites. Crescentic and circumferential lymphocytic phlebitis is more common in viable bowel than in the ischemic segment. A nonsignificant trend was found for increased crescentic morphology between intact bowel remote from the ischemic focus compared with that adjacent to the ischemic focus. Hallmarks of ischemic bowel are necrotizing phlebitis and thrombi formation. Thrombophlebitis morphology is distinctly different in viable and ischemic bowel, changing from the classic lymphocytic to necrotizing lesions respectively.