Developing and Validating a Multivariable Prognostic-Predictive Classifier for Treatment Escalation of Oropharyngeal Squamous Cell Carcinoma: The PREDICTR-OPC Study.

PURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.

The Characteristics of Real-time Transvaginal Sono-elastography in Endometrial Cancer.

Background: Endometrial cancer is the most common gynecological cancer among women in developed countries. Sono-elastography is an extended ultrasonographic technique that has been shown to be useful in a wide range of conditions ranging from breast, prostate, and thyroid nodules to chronic liver disease and musculoskeletal conditions. The aim of this study is to compare the sonoelastographic features of endometrial malignancy and normal endometrium. Methods: This case-control observational study was conducted at a single institution. Participants with histologically proven endometrial cancer according to the results from microcurettage or hysteroscopic biopsy and scheduled for total hysterectomy were included as cases, while asymptomatic women scheduled for routine screening ultrasound examination were recruited as controls. Both cases and controls underwent conventional B-mode transvaginal ultrasonography and strain elastography. Demographic, ultrasonographic, and histopathologic findings were analyzed. Results: A total of 29 endometrial cancer patients (cases) and 28 normal females (controls) were included in the analysis. There was no significant difference in the mean age between the two groups, but the mean body weight was significantly higher in the case group (P < 0.001). The strain ratio and elastographic thickness ratio of the endometrium were statistically significantly different between the case and the control group (P ≤ 0.05) due to increased endometrial stiffness in cancer patients as compared to the normal group. Conclusion: Our results suggest that endometrial cancer can result in increased stiffness that is detectable by transvaginal sonoelastography. Sonoelastography may serve as an adjunct to conventional ultrasound in evaluating the endometrium of women with abnormal uterine bleeding.

A Cervical Smear Scare due to Monsel's Solution: A Case Report.

Monsel's solution has been in use since the end of the 19th century for its valuable property of creating hemostasis in minor disruptions of the epithelium. Its styptic effect was first described by Leon Monsel, a pharmacist in the French army, in a letter dated on October 13, 1852. Containing ferric subsulphate, it is used as a topical hemostatic agent in minor procedures such as biopsies in gynecology, proctology, dermatology, otorhinolaryngology and odontology. A 28-year-old nulliparous woman, with a known history of adenomyosis, had presented for sudden heavy intermenstrual vaginal bleeding. Examination revealed a bleeding Nabothian cyst. Monsel's solution application helped stop the bleeding. She returned 3 days later with persistent heavy vaginal bleeding. Examination showed active oozing from the Nabothian cyst. A cervical smear and a human papillomavirus (HPV) swab were taken, and vaginal packing was inserted. The cervical smear result was reported as atypical cells, suspicious for malignancy. Colposcopy performed showed a grade 2 acetowhite lesion, suspicious for cervical intraepithelial neoplasia (CIN) III/microinvasive disease. However, punch biopsies of the cervix revealed only CIN I/koilocytosis. The patient was counselled and subsequently underwent a laser cone biopsy, which showed CIN I with clear margins. The discrepant results between the cervical smear and the cone biopsy prompted a review of the cervical smear and cervical histology; and a relook at the chronology of events. The cytological features observed in the initial cervical smear could be explained by the interference from the Monsel's solution, which was applied just 3 days before the cervical smear. In cases where Monsel's solution has been used for hemostasis, it is best to delay taking a cervical smear or a biopsy for at least 3 weeks as the histologic effect of Monsel's solution may persist for up to that duration of time in tissues.

Treatment failure with propranolol for subglottic haemangioma.

The use of propranolol for the treatment of subglottic haemangioma has become hugely popular due to its effectiveness and safety profile. We report a case of 7-month-old boy who presented with stridor and histopathology suggestive of subglottic haemangioma following microlaryngoscopy and bronchoscopy (MLB). However, he did not respond to propranolol treatment. This could be due to an older age of propranolol commencement. In general, early commencement of propranolol is necessary when diagnosis of symptomatic infantile haemangioma is made to achieve maximal improvement in symptoms and prevent further proliferation. There should be a high index of suspicion for subglottic haemangioma in children presenting with chronic biphasic stridor, with early MLB and diagnosis. This will allow early treatment, giving the best chance to avoid our situation.

A Rare Case of Ovarian Follicular Lymphoma: Incidental Finding in a Woman With Postmenopausal Bleeding.

Ovarian lymphoma is an uncommon malignancy with the incidence of primary ovarian lymphoma being ever rarer. Majority of patients with ovarian lymphoma tend to present with symptoms of abdominal distension, abdominal pain, loss of weight or appetite, and are usually found to have an ovarian mass. Postmenopausal bleeding (PMB) is not a symptom that is usually associated with ovarian pathology. This case report gives an account of how the patient presented to us, and the investigations and treatments offered that led to the final outcome.

Validation of digital pathology imaging for primary histopathological diagnosis.

AIMS: Digital pathology (DP) offers advantages over glass slide microscopy (GS), but data demonstrating a statistically valid equivalent (i.e. non-inferior) performance of DP against GS are required to permit its use in diagnosis. The aim of this study is to provide evidence of non-inferiority. METHODS AND RESULTS: Seventeen pathologists re-reported 3017 cases by DP. Of these, 1009 were re-reported by the same pathologist, and 2008 by a different pathologist. Re-examination of 10 138 scanned slides (2.22 terabytes) produced 72 variances between GS and DP reports, including 21 clinically significant variances. Ground truth lay with GS in 12 cases and with DP in nine cases. These results are within the 95% confidence interval for existing intraobserver and interobserver variability, proving that DP is non-inferior to GS. In three cases, the digital platform was deemed to be responsible for the variance, including a gastric biopsy, where Helicobacter pylori only became visible on slides scanned at the ×60 setting, and a bronchial biopsy and penile biopsy, where dysplasia was reported on DP but was not present on GS. CONCLUSIONS: This is one of the largest studies proving that DP is equivalent to GS for the diagnosis of histopathology specimens. Error rates are similar in both platforms, although some problems e.g. detection of bacteria, are predictable.

Identification of brown adipose tissue using MR imaging in a human adult with histological and immunohistochemical confirmation.

OBJECTIVE: Manipulation of human brown adipose tissue (BAT) represents a novel therapeutic option for diabesity. The aim of our study was to develop and test a novel magnetic resonance (MR) imaging-based method to identify human BAT, delineate it from white adipose tissue, and validate it through immunohistochemistry. DESIGN: A 25-year old Caucasian female with hyperparathyroidism-jaw tumor syndrome underwent parathyroidectomy. An (18)fluoro-2-deoxyglucose positron emission tomography (PET)-computed tomography (CT) scan performed after surgery ruled out malignancy but showed avid uptake within the mediastinum, neck, supraclavicular fossae, and axillae, consistent with BAT. Immunohistochemical staining using uncoupling protein-1 antibody was performed on one fat sample obtained from the suprasternal area during parathyroidectomy. Subsequently, serial MR scans were performed. Retrospectively, regions of interest (ROIs) were identified on MR corresponding to areas of high uptake on PET-CT. Prospectively, ROIs were identified on MR based on signal intensity and appearance and compared with PET-CT. RESULTS: Of 111 retrospectively identified ROIs from PET-CT, 93 (83.8%) showed corresponding low MR signal: 25 of 25 mediastinum (100%), 29 of 31 neck (93.5%), 31 of 41 supraclavicular (75.6%), and 8 of 14 axillae (57%). Prospectively, 47 of 54 ROIs identified on MR (87%) showed a corresponding increased uptake on PET-CT. Serendipitously, the sample obtained at surgery corresponded with high uptake and low signal on subsequent PET and MR, respectively, and immunohistochemistry confirmed BAT. CONCLUSION: We provide the first report for the reliable use of MR to identify BAT in a living human adult, with histological/immunohistochemical confirmation. Our data demonstrate proof of concept to support the development of MR as a safe, reproducible imaging modality for human BAT.

Antigen processing and correlation with immunological response in vulval intraepithelial neoplasia--a study of CD1a, CD54 and LN3 expression.

OBJECTIVE: To study the antigen-presenting cells and co-stimulatory factors (HLA class 2 antigen and adhesion molecule) in different grades of vulval intraepithelial neoplasia (VIN). MATERIAL AND METHODS: Forty-five histology specimens were obtained from 21 women who had previously undergone vulval biopsies for VIN and included 12 specimens of VIN I, 5 of VIN II and 28 of VIN III. The CD1a (Langerhans cell/antigen-presenting cell marker) and co-stimulatory factors--HLA Class 2 antigens (LN3) and the adhesion molecule (CD54)--were semi-quantitatively analyzed in all the specimens. Pearson Chi-squared test was used for statistical analysis. RESULTS: CD1a was increased in 11/12 (91.6%) biopsies with VIN I, in 3/5 (60%) of VIN II and in 4/28(14.3%) of VIN III. There was thus an inverse correlation between CD1a and severity of VIN (Pearson Chi-squared = 26.876, P = 0.001). Qualitatively, there was a basal location of CD1a-positive cells in normal epithelium but had a haphazard distribution in both low grade and high grade VIN. There was no statistical significance in the distribution of LN3 and CD54 in different grades of VIN. CONCLUSIONS: This study shows an alteration in the numbers and spatial arrangement of CD1a-positive Langerhans/antigen-presenting cells in different grades of VIN. There is an increase in the number of cells with CD1a expression in low grade VIN and a decrease in the number of these cells in high grade VIN. Reduction in CD1a expression may reflect the inability of the host to mount an adequate immune response due to reduced antigen presentation in high grade VIN.

A Case of Ovarian Fibromatosis and Massive Ovarian Oedema Associated With Intra-Abdominal Fibromatosis, Sclerosing Peritonitis and Meig's Syndrome.

PURPOSE: To discuss a case of ovarian fibromatosis/massive ovarian oedema, intra-abdominal fibromatosis, sclerosing peritonitis and Meig's syndrome. To review the reported therapeutic options. PATIENTS: Case report of a 27-year-old female with the combined pathology of ovarian fibromatosis/massive ovarian oedema, intra-abdominal fibromatosis, sclerosing peritonitis and Meig's syndrome. METHODS: This patient was treated with supportive care and cytotoxic chemotherapy. RESULTS: Despite the benign nature of the ovarian pathology, this patient presented with life-threatening complications. Response to treatment was probably multi-factorial combining the effects of cytotoxics, use of steroids and good supportive care. She remains in complete remission 4 years post completion of chemotherapy. CONCLUSION: There are reports in the literature of ovarian fibromatosis/massive ovarian oedema, luteinised thecomas, intraabdominal fibromatosis and Meig's syndrome occurring together in a variety of combinations. Treatment has been described with radiotherapy, cytotoxic and non-cytotoxic chemotherapy regimens. This case provides a link between ovarian fibromatosis/massive ovarian oedema, intra-abdominal fibromatosis, sclerosing peritonitis and Meig's syndrome not previously described.