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.

Fluorescence Visualization-Guided Surgery for Early-Stage Oral Cancer.

IMPORTANCE: The prevalence of genetically altered cells in oral cancers has a negative influence on the locoregional recurrence rate and lowers survival. Fluorescence visualization (FV) can identify clinically occult, high-risk oral lesions by allowing health care professionals and surgeons to visualize and map occult disease. This process may improve overall survival by decreasing rates of locoregional recurrence. OBJECTIVE: To assess the efficacy of FV-guided surgery in reducing locoregional recurrence and improving overall survival. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, case-control observational study was conducted on patients registered at a single oral oncology clinic from September 1, 2004, to August 31, 2009. The study included 246 patients 18 years or older with a diagnosis of a high-grade lesion (severe dysplasia or carcinoma in situ) or squamous cell carcinoma of less than 4 cm who underwent curative surgical treatment with at least 1 follow-up visit. Among these patients, 154 underwent surgery with FV guidance (FV group) and the other 92 underwent conventional surgery (control group). Demographic and lesional characteristics and outcomes were collected, and the key factors for the efficacy of FV-guided surgery were examined. Follow-up was completed on December 31, 2011, and data were analyzed from May 1 to November 30, 2013. MAIN OUTCOMES AND MEASURES: Local recurrence of oral lesions with a histologic grade of severe dysplasia or higher, the presence of regional failure (ie, a metastatic lesion in the cervical lymph nodes), or disease-free survival after surgery. RESULTS: Among the 246 patients included in the study (mean [SD] age, 60 [12] years; 108 women and 138 men), 156 had squamous cell carcinoma and 90 had high-grade lesions. There were no significant differences between the FV (n = 154) and control (n = 92) groups in age, smoking history, anatomical site of the lesion, tumor size, and previous oral cancer. Among the 156 patients with squamous cell carcinoma, the 92 patients in the FV group showed significant reduction in the 3-year local recurrence rate, from 40.6% (26 of 64 patients) to 6.5% (6 of 92 patients) (P < .001). Among the 90 patients with high-grade lesions, the 62 patients in the FV group showed a reduction in local recurrence rate from 11 of 28 patients (39.3%) to 5 of 62 patients (8.1%) (P < .001). The data also indicated that, compared with conventional surgery, the FV-guided approach for squamous cell carcinoma was associated with less regional failure (14 of 92 patients [15.2%] vs 16 of 64 [25.0%]; P = .08) and death (12 of 92 patients [13.0%] vs 13 of 64 [20.3%]; P = .22), although these differences were not statistically significant. CONCLUSIONS AND RELEVANCE: In this study, the use of FV as part of the surgical margin decision process significantly reduced the rate of local recurrence in preinvasive high-grade and early-stage oral cancers. An ongoing multicenter, phase 3, randomized surgical trial has completed accrual, and the data will be used to validate the results of this study.

Low-grade intraductal carcinoma of the lacrimal gland.

Intraductal carcinoma has been described in the salivary glands as a relatively benign tumour with low-grade histopathologic features. To our knowledge, this tumour has not previously been reported in the lacrimal gland. We report the first case of low-grade intraductal carcinoma occurring in the lacrimal gland. This tumour was discovered incidentally on neuro-imaging in an asymptomatic 65-year-old patient. Incisional biopsy revealed uniform, polygonal cells with eosinophilic cytoplasm and minimal nuclear atypia, arranged in solid, cribiform and micropapillary nests. The patient underwent complete surgical excision with no evidence of recurrence at 8 months of follow-up.

EWSR1 genetic rearrangements in salivary gland tumors: a specific and very common feature of hyalinizing clear cell carcinoma.

The Ewing sarcoma breakpoint region 1 (EWSR1) is translocated in many sarcomas. Recently, its rearrangement has been described in salivary gland hyalinizing clear cell carcinomas (HCCCs) and in a subset of soft tissue myoepitheliomas. This study examines the presence of the EWSR1 rearrangement in a variety of salivary gland lesions including classic myoepitheliomas and HCCCs. Using a tissue microarray and whole-mount sections, fluorescence in situ hybridization (FISH) was performed on a variety of salivary gland lesions including HCCCs. The EWSR1 rearrangement was detected in 87% of HCCCs (13 of 15); all other salivary gland lesions including classic myoepitheliomas had intact EWSR1. Patients with HCCCs with rearranged EWSR1 included 1 man, 10 women, and 2 of unknown sex. Ages ranged from 35 to 83 years; the tumor size ranged from 0.8 to 5.5 cm, and the involved locations included: palate (2), base of the tongue (2), mandible (2), submandibular gland (2), lip (1), floor of the mouth (1), sublingual gland (1), inner cheek (1), and nasopharynx (1). All HCCCs were composed of sheets and nests of monotonous cells with clear cytoplasm within a hyalinized stroma. All tested cases were immunoreactive with antibodies to p63 and were nonreactive with antibodies to more conventional myoepithelial antigens (e.g., smooth muscle actin and S100 protein). These findings show that the EWSR1 rearrangement is almost a defining feature of HCCCs and also confirm that classic salivary gland myoepitheliomas are distinct from these tumors and do not share a pathogenetic relationship with their soft tissue counterparts.

Canadian Optically-guided approach for Oral Lesions Surgical (COOLS) trial: study protocol for a randomized controlled trial.

BACKGROUND: Oral cancer is a major health problem worldwide. The 5-year survival rate ranges from 30-60%, and has remained unchanged in the past few decades. This is mainly due to late diagnosis and high recurrence of the disease. Of the patients who receive treatment, up to one third suffer from a recurrence or a second primary tumor. It is apparent that one major cause of disease recurrence is clinically unrecognized field changes which extend beyond the visible tumor boundary. We have previously developed an approach using fluorescence visualization (FV) technology to improve the recognition of the field at risk surrounding a visible oral cancer that needs to be removed and preliminary results have shown a significant reduction in recurrence rates. METHOD/DESIGN: This paper describes the study design of a randomized, multi-centre, double blind, controlled surgical trial, the COOLS trial. Nine institutions across Canada will recruit a total of 400 patients with oral severe dysplasia or carcinoma in situ (N = 160) and invasive squamous cell carcinoma (N = 240). Patients will be stratified by participating institution and histology grade and randomized equally into FV-guided surgery (experimental arm) or white light-guided surgery (control arm). The primary endpoint is a composite of recurrence at or 1 cm within the previous surgery site with 1) the same or higher grade histology compared to the initial diagnosis (i.e., the diagnosis used for randomization); or 2) further treatment due to the presence of severe dysplasia or higher degree of change at follow-up. This is the first randomized, multi-centre trial to validate the effectiveness of the FV-guided surgery. DISCUSSION: In this paper we described the strategies, novelty, and challenges of this unique trial involving a surgical approach guided by the FV technology. The success of the trial requires training, coordination, and quality assurance across multiple sites within Canada. The COOLS trial, an example of translational research, may result in reduced recurrence rates following surgical treatment of early-stage oral cancer with significant impacts on survival, morbidity, patients' quality of life and the cost to the health care system. TRIAL REGISTRATION: Clinicaltrials.gov NCT01039298.

Familial adenomatous polyposis-rendering a diagnosis based on recognition of an unusual primary thyroid neoplasm.

It has been well established in the literature that the cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) has been observed with higher frequency in familial adenomatous polyposis (FAP) patients. In the usual setting, patients with FAP are identified based on their germline mutations and the diagnosis of thyroid neoplasm is made after the FAP diagnosis. We herein report a case in which the recognition of a CMVPTC led to the initial diagnosis of FAP. The histological and clinical features of CMVPTC are reviewed with emphasis on its relationship to FAP.

Primary middle ear Epstein-Barr virus-related lymphoepithelial carcinoma: case reports and systematic review.

OBJECTIVES/HYPOTHESIS: To report two cases of primary lymphoepithelial carcinoma in the middle ear and to determine the optimal treatment for such lesions. STUDY DESIGN/METHODS: Case reports and a systematic review of the literature. RESULTS: Primary lymphoepithelial carcinoma in the middle ear is an exceptionally rare condition with only two other cases reported in the literature. There appears to be an association with Epstein-Barr virus infection and in those patients originating from the Guangdong province of China, much as is the case for similar lesions found in the nasopharynx. Piecemeal rather than en bloc excision, in combination with adjuvant radiotherapy, appears to adequately control the disease. CONCLUSIONS: Primary lymphoepithelial carcinoma of the middle ear is a rare lesion, which when treated has a good prognosis.

Epithelial lacrimal gland tumors: pathologic classification and current understanding.

OBJECTIVE: To apply the updated epithelial salivary gland classification scheme to a large cohort of lacrimal gland tumors so as to provide an updated lacrimal gland tumor classification scheme. METHODS: A retrospective multicenter cohort study of 118 cases of epithelial neoplasia was undertaken. Main outcome measures included pathologic analysis, subtyping, and survival. RESULTS: Of 118 cases, 17 (14%) were reclassified using the proposed expanded classification scheme based on the current World Health Organization classification of salivary gland tumors. The most frequent neoplasms were pleomorphic adenoma and adenoid cystic carcinoma, of which we highlight more unusual histologic features. Three tumors were found to be unclassifiable with the updated scheme, with 2 having histologically malignant features. Deficiencies and variations in pathologic assessment were noted. Variation in the histologic findings of pleomorphic adenoma and assessment of the extent of invasion of carcinoma ex pleomorphic adenoma were highlighted. CONCLUSIONS: The use of the more histologically diverse classification of salivary gland tumors can be successfully applied to the epithelial lacrimal gland neoplasms. This expanded classification system led to reclassifying 14% of cases. Currently, there are no consistent pathologic standards for processing and evaluating these lesions.

Biopsy and histopathologic diagnosis of oral premalignant and malignant lesions.

Accurate diagnosis of premalignant or malignant oral lesions depends on the quality of the biopsy, adequate clinical information and correct interpretation of the biopsy results. The purpose of this paper is to review the procedures for obtaining appropriate biopsy samples, and the criteria for diagnosing and grading dysplasias. The World Health Organization's description of the architectural and cytologic epithelial changes that characterize dysplasia is detailed, and guidelines for following up patients with premalignant and malignant lesions are provided. The benefits of using the centralized services and expertise of the British Columbia Oral Biopsy Service are also reviewed.

Combined diffusion-weighted and dynamic contrast-enhanced MRI for prostate cancer diagnosis--correlation with biopsy and histopathology.

PURPOSE: To determine whether the combination of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI provides higher diagnostic sensitivity for prostate cancer than each technique alone. MATERIALS AND METHODS: Fourteen patients with a clinical suspicion of prostate cancer underwent endorectal MRI on a 1.5T scanner prior to transrectal ultrasound (TRUS)-guided biopsies. The average values of the apparent diffusion coefficient (ADC, calculated from b-values of 0 and 600), K(trans), v(e), maximum gadolinium (Gd) concentration, onset time, mean gradient, and maximum enhancement were determined. Correlation with histology was based on biopsy (six patients) and prostatectomy specimen (eight patients) results. The Tukey-Kramer test was used for statistical analysis. RESULTS: The average values of all MRI parameters, except v(e) and maximum Gd concentration, showed significant differences between tumor and normal prostate. The sensitivity and specificity values were respectively 54% (35-72%) and 100% (95-100%) for the ADC data, and 59% (39-77%) and 74% (63-83%) for the DCE data. When both ADC and DCE results were combined, the sensitivity increased to 87% (68-95%) and specificity decreased to 74% (62-83%). CONCLUSION: All but two DW- and DCE-MRI parameters showed significant differences between tumor and normal prostate. Combining both techniques provides better sensitivity, with a small decrease in specificity.

Multifocal idiopathic fibrosclerosis: treatment of 2 cases with cyclosporine.

We describe 2 cases of multifocal idiopathic fibrosclerosis treated successfully with cyclosporine. The first patient presented with chronic abdominal pain and was subsequently found to have retroperitoneal fibrosis with ureteral obstruction. Other findings included cholangiolar fibrosis, retroorbital pseudotumors, submandibular gland enlargement, subcutaneous fibrotic masses, and elevated erythrocyte sedimentation rate (ESR) and serum creatinine. He initially responded well to temporary ureteral stenting followed by combination therapy with steroids and cyclosporine. He relapsed when cyclosporine was stopped, but subsequently remitted completely when cyclosporine was reintroduced. The second patient presented with long-standing abdominal pain with retroperitoneal fibrosis, submandibular gland enlargement, and an enlarged pancreas with a localized mass, all of which improved significantly with 6 months of therapy with cyclosporine. Cyclosporine was well tolerated with no significant side effects in the 2 patients. A review of the literature is presented.

Cytokeratin subtypes in thyroid tumours: immunohistochemical study with emphasis on the follicular variant of papillary carcinoma.

OBJECTIVE: The follicular variant of papillary thyroid carcinoma (FV-PTC) may be difficult to differentiate from other thyroid neoplasms with follicular architecture such as follicular adenoma, follicular carcinoma, and dominant nodules in nodular goitre. Obvious differences in treatment and expected outcome between these lesions mandate that the distinction between them be made accurately. To decrease the subjectivity of this differential diagnosis, we undertook this study to determine if any difference in cytokeratin profile exists between FV-PTC and other follicular lesions of the thyroid gland. DESIGN: Immunohistochemical analysis based on a retrospective pathology review. SETTING: Vancouver General Hospital, Vancouver, BC. METHODS: The files of the Vancouver General Hospital anatomic pathology laboratory were searched for cases of typical papillary thyroid carcinoma (PTC), FV-PTC, follicular adenoma, follicular carcinoma, and nodular goitre. The slides and reports were reviewed, and those cases with confirmed diagnosis and adequate tissue were selected for inclusion in the study. Monoclonal antibodies to cytokeratin 19 (CK19), 20 (CK20), and 7 (CK7) were applied to formalin-fixed, paraffin-embedded tissue sections. RESULTS: All cases of PTC, including FV-PTC, as well as all follicular adenomas, follicular carcinomas, and nodular goitres, stained positively for CK7 and, except for a single follicular carcinoma, were negative for CK20. CK19 decorated almost all PTCs, including FV-PTC, although the staining was sometimes focal. The majority of the cases of follicular adenoma, follicular carcinoma, and nodular goitre were negative or showed focal staining with CK19, although occasional cases showed diffuse positivity. CONCLUSIONS: CK19 strongly stains the majority of PTC, including FV-PTC, in a diffuse manner. However, overlap with the staining seen in other follicular lesions limits its utility in a routine diagnostic setting.