Transoral laser microsurgery and radiotherapy for oropharyngeal squamous cell carcinoma: Equitable survival and enhanced function compared with contemporary standards of care.

INTRODUCTION: We describe the 5-year oncological and functional outcomes of transoral laser microsurgery, neck dissection (TLM + ND) and adjuvant radiotherapy (PORT) used to treat patients with oropharyngeal carcinoma. The effectiveness of external carotid artery (ECA) ligation in reducing post-operative bleeding, and fibrin glue following ND in reducing wound drainage and length of hospital stay is reported. MATERIALS AND METHODS: This retrospective case review of consecutive patients undergoing TLM between 2006 and 2017 used the Kaplan-Meier Estimator and Log-Rank Test for univariate, time-to-event analyses, and Cox-Proportionate Hazard modelling for multivariate analysis. RESULTS: 264 consecutive patients were included. Mean follow-up was 49.4 months. 219 (82.9%) patients received PORT. Five-year overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) rates were 74.9%, 73.7%, and 86.2%, respectively. Five-year locoregional control was 89.4%. 65.5% of cases were Human papillomavirus associated (HPV+), for whom OS, DFS and DSS was 85.6%, 84.7% and 92.7%, respectively, and demonstrated significantly higher OS (hazard ratio (HR) 0.28, CI 0.16-0.49, p < 0.0001), DFS (HR 0.28, CI 0.17-0.47, p < 0.0001) and DSS (HR 0.2, CI 0.09-0.44, <0.001). Post-operative oropharyngeal bleeding occurred in 23 patients (8.7%), of which 5 were major/severe, in patients without ECA ligation. Fibrin glue significantly reduced neck drain output (p < 0.001), and length of hospital stay (p < 0.001). One-year gastrostomy dependence rate was 2.3%. CONCLUSIONS: TLM + ND + PORT results in favourable 5-year survival and locoregional control rates, and low feeding tube dependency rates. ECA ligation and fibrin glue appear to reduce major post-operative haemorrhage, wound drainage and length of hospital stay.

Prognostic impact of intra-field heterogeneity in oral squamous cell carcinoma.

Genetic heterogeneity displayed by tumour cells (intratumoural heterogeneity, ITH) represents a diagnostic challenge when assessing tumour mutational profile. In oral squamous cell carcinoma (OSCC), ITH may be found both in tumour cells and in adjacent mucosa. Genetic heterogeneity of the adjacent mucosa can be interpreted as evidence of the field cancerization (field heterogeneity, FH). The aim of the study was to investigate the impact of intratumoural and intrafield heterogeneity on locoregional control. Ten OSCC patients (5 recurrent and 5 nonrecurrent) were studied. Multiple areas were sampled from the bulk of the tumour and the adjacent nonneoplastic mucosa. A panel of 10 tumour-specific OSCC driver genes was analysed for each sample and was used to calculate heterogeneity. Values were compared among recurrent and nonrecurrent OSCC. Mutational analysis highlighted that a single tumour sample has limited accuracy in assessing the genetic profiles of tumours. High values of ITH considering shared mutations between specimens were found in both recurrent and non-recurrent OSCC (p = 0.095). On the contrary, the intrafield genetic heterogeneity was significantly less frequently in the non-recurrent OSCC group (p = 0.032). Heterogeneity within each specimen calculated with variant allele frequency confirmed that there was better discrimination between recurrent and nonrecurrent groups using nonneoplastic adjacent mucosa than tumour tissue (p value 0.0006 and 0.0048 respectively). In agreement with the theory of field cancerization, intrafield genetic heterogeneity correlates with a higher risk of developing loco-regional recurrences and second primaries. In order to reduce the ITH effects, analysis of multiple tumour areas should be encouraged.

Clinical evaluation and treatment of phaeochromocytoma.

Phaeochromocytoma and extra adrenal paraganglioma are rare neuroendocrine tumours and have the potential to secrete adrenaline, noradrenaline and dopamine causing a myriad of clinical symptoms. Prompt diagnosis is essential for clinicians and requires a multidisciplinary specialist approach for the clinical and laboratory investigation, diagnosis, treatment and follow-up of patients. This paper is an integrated review of the clinical and laboratory evaluation and treatment of patients suspected to have phaeochromocytoma or paraganglioma, highlighting recent developments and best practices from recent published clinical guidelines.

Non-infectious Inflammatory Lesions of the Sinonasal Tract.

This review covers the histopathology and pathogenesis of non-infectious inflammatory diseases of the sinonasal tract, in particular, sarcoidosis, granulomatous vasculitides Wegener, Churg-Strauss), relapsing polychondritis, eosinophilic angiocentric fibrosis, chronic rhinosinusitis and nasal perforations. Molecular associations and mechanisms are emphasised to assist pathologists to put their observations into the context of clinical, genetic and environmental influences on patients' diseases.

Rapid skeletal turnover in a radiographic mimic of osteopetrosis.

Among the high bone mass disorders, the osteopetroses reflect osteoclast failure that prevents skeletal resorption and turnover, leading to reduced bone growth and modeling and characteristic histopathological and radiographic findings. We report an 11-year-old boy with a new syndrome that radiographically mimics osteopetrosis (OPT), but features rapid skeletal turnover. He presented at age 21 months with a parasellar, osteoclast-rich giant cell granuloma. Radiographs showed a dense skull, generalized osteosclerosis and cortical thickening, medullary cavity narrowing, and diminished modeling of tubular bones. His serum alkaline phosphatase was >5000 IU/L (normal <850 IU/L). After partial resection, the granuloma re-grew but then regressed and stabilized during 3 years of uncomplicated pamidronate treatment. His hyperphosphatasemia transiently diminished, but all bone turnover markers, especially those of apposition, remained elevated. Two years after pamidronate therapy stopped, bone mineral density (BMD) Z-scores reached +9.1 and +5.8 in the lumbar spine and hip, respectively, and iliac crest histopathology confirmed rapid bone remodeling. Serum multiplex biomarker profiling was striking for low sclerostin. Mutation analysis was negative for activation of lipoprotein receptor-related protein 4 (LRP4), LRP5, or TGFß1, and for defective sclerostin (SOST), osteoprotegerin (OPG), RANKL, RANK, SQSTM1, or sFRP1. Microarray showed no notable copy number variation. Studies of his nonconsanguineous parents were unremarkable. The etiology and pathogenesis of this unique syndrome are unknown.

Characterization of Wnt/ß-catenin signaling in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and accounts for about 5% of all malignant paediatric tumours. ß-Catenin, a multifunctional nuclear transcription factor in the canonical Wnt signaling pathway, is active in myogenesis and embryonal somite patterning. Dysregulation of Wnt signaling facilitates tumour invasion and metastasis. This study characterizes Wnt/ß-catenin signaling and functional activity in paediatric embryonal and alveolar RMS. Immunohistochemical assessment of paraffin-embedded tissues from 44 RMS showed ß-catenin expression in 26 cases with cytoplasmic/membranous expression in 9/14 cases of alveolar RMS, and 15/30 cases of embryonal RMS, whereas nuclear expression was only seen in 2 cases of embryonal RMS. The potential functional significance of ß-catenin expression was tested in four RMS cell lines, two derived from embryonal (RD and RD18) RMS and two from alveolar (Rh4 and Rh30) RMS. Western blot analysis demonstrated the expression of Wnt-associated proteins including ß-catenin, glycogen synthase kinase-3ß, disheveled, axin-1, naked, LRP-6 and cadherins in all cell lines. Cell fractionation and immunofluorescence studies of the cell lines (after stimulation by human recombinant Wnt3a) showed reduced phosphorylation of ß-catenin, stabilization of the active cytosolic form and nuclear translocation of ß-catenin. Reporter gene assay demonstrated a T-cell factor/lymphoid-enhancing factor-mediated transactivation in these cells. In response to human recombinant Wnt3a, the alveolar RMS cells showed a significant decrease in proliferation rate and induction of myogenic differentiation (myogenin, MyoD1 and myf5). These data indicate that the central regulatory components of canonical Wnt/ß-catenin signaling are expressed and that this pathway is functionally active in a significant subset of RMS tumours and might represent a novel therapeutic target.

Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.

Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: sensitivity, specificity, and prognostic discrimination.

PURPOSE: Human papillomavirus-16 (HPV16) is the causative agent in a biologically distinct subset of oropharyngeal squamous cell carcinoma (OPSCC) with highly favorable prognosis. In clinical trials, HPV16 status is an essential inclusion or stratification parameter, highlighting the importance of accurate testing. EXPERIMENTAL DESIGN: Fixed and fresh-frozen tissue from 108 OPSCC cases were subject to eight possible assay/assay combinations: p16 immunohistochemistry (p16 IHC); in situ hybridization for high-risk HPV (HR HPV ISH); quantitative PCR (qPCR) for both viral E6 RNA (RNA qPCR) and DNA (DNA qPCR); and combinations of the above. RESULTS: HPV16-positive OPSCC presented in younger patients (mean 7.5 years younger, P = 0.003) who smoked less than HPV-negative patients (P = 0.007). The proportion of HPV16-positive cases increased from 15% to 57% (P = 0.001) between 1988 and 2009. A combination of p16 IHC/DNA qPCR showed acceptable sensitivity (97%) and specificity (94%) compared with the RNA qPCR "gold standard", as well as being the best discriminator of favorable outcome (overall survival P = 0.002). p16 IHC/HR HPV ISH also had acceptable specificity (90%) but the substantial reduction in its sensitivity (88%) impacted upon its prognostic value (P = 0.02). p16 IHC, HR HPV ISH, or DNA qPCR was not sufficiently specific to recommend in clinical trials when used in isolation. CONCLUSIONS: Caution must be exercised in applying HPV16 diagnostic tests because of significant disparities in accuracy and prognostic value in previously published techniques.

Polypoid pseudomyxoma of ascending aorta after replacement with a Dacron graft.

We report a 58-year-old man who had a multi-lobulated pseudomyxomatous lesion in his ascending aorta 6 months after his root and ascending aorta was replaced by a Dacron graft.

Retropharyngeal angiomyxoma presenting with transoral intussusception.

We report on a 66-year-old female who presented with a massive lesion protruding from her mouth and obstructing her airway, which was found to be an angiomyxoma arising from the retropharyngeal tissue.

Survival of patients with neck recurrence following radical neck dissection: utility of a second neck dissection?

Treatment of neck recurrence following radical neck dissection is extremely difficult. Retrospective review of 699 radical neck dissections was performed. Recurrence rates, host, tumor, treatment factors, and survival were analyzed. One hundred nineteen patients who had undergone radical neck dissections had recurrence, 69 were considered candidates for salvage surgery. Factors that increased the risk of neck recurrence were neck node (N) status and no adjuvant radiotherapy. Factors associated with radical salvage treatment were young age, good general condition, and low recurrent N classification. Five-year survival for salvage neck dissection was 31%. Young patients and low T and N classification did well. Low recurrent N classification and salvage surgery were associated with good prognosis for recurrence. In our study, radical neck dissection has a regional failure rate of 20%, a third of recurrence cases were offered curative treatment. Of these, 31% were cured with salvage surgery.

Retinoblastoma gene abnormalities in early laryngeal cancer.

The retinoblastoma gene (Rb) is postulated to be important in carcinoma of the larynx. Its cellular protein (pRb) is involved in regulation of the cell cycle and may be influential in the cells response to irradiation injury. From the University of Liverpool Head and Neck Database we identified 35 patients with a T2 N0 laryngeal squamous carcinoma whom received primary irradiation and had a minimum of 5 years follow up. Laser capture microdissection was performed on paired normal and tumour biopsy material to analyse for loss of heterozygosity (LOH) and microsatellite instability (MI) of the Rb gene and immunohistochemistry (IHC) was carried out to detect pRb expression. Of 35 tumours, 13 were normal, 12 had MI and 5 had LOH of the Rb gene. Abnormalities at the Rb locus did not correlate with loss of pRb expression. There was also no significant difference between the distribution of normal and abnormal gene sequences and whether or not the primary laryngeal tumour recurred after radiotherapy. Rb gene abnormalities occurred in one third of T2 N0 laryngeal carcinomas. These were not in isolation predictive of cure by radiotherapy.

Inflammatory pseudotumor of the Kidney.

BACKGROUND: Inflammatory pseudotumor of the kidney or inflammatory myofibroblastic tumor (IMT) is composed of spindle cells admixed with variable amount of proliferating myofibroblasts, fibroblasts, extracellular collagen, lymphocytes and plasma cells. This mainly affects the urinary bladder or prostate. Renal involvement is rare. CASE PRESENTATION: A 56 year-old man was diagnosed with asymptomatic left sided hydronephrosis while being investigated for rheumatoid arthritis. CT scan imaging showed ill defined fascial plains around the kidney and thickening around the renal hilum suggestive of localized inflammatory change. Worsening intermittent left loin pain with increasing hydronephrosis, significant cortical thinning and marked deterioration of renal function necessitated nephrectomy. Macroscopy showed a hydronephrotic fibrotic kidney with microscopy and immunohistochemistry consistent with a histological diagnosis of IMT. CONCLUSION: We report a case of an inflammatory pseudotumor of the kidney. It is unique in that the patient presented with painless hydronephrosis followed two years later with progressive deterioration in renal function and worsening loin pain.

An artificial neural network improves prediction of observed survival in patients with laryngeal squamous carcinoma.

The accepted method of modelling and predicting failure/survival, Cox's proportional hazards model, is theoretically inferior to neural network derived models for analysing highly complex systems with large datasets. A blinded comparison of the neural network versus the Cox's model in predicting survival utilising data from 873 treated patients with laryngeal cancer. These were divided randomly and equally into a training set and a study set and Cox's and neural network models applied in turn. Data were then divided into seven sets of binary covariates and the analysis repeated. Overall survival was not significantly different on Kaplan-Meier plot, or with either test model. Although the network produced qualitatively similar results to Cox's model it was significantly more sensitive to differences in survival curves for age and N stage. We propose that neural networks are capable of prediction in systems involving complex interactions between variables and non-linearity.

Atypical and malignant peripheral nerve-sheath tumors of the brachial plexus: report of three cases and review of the literature.

Tumor involvement of the brachial plexus is uncommon. The most common intrinsic neoplasms involving the brachial plexus are benign neurilemmomas and neurofibromas that are usually associated with neurofibromatosis-1 (NF-1). Solitary neurofibromas unassociated with NF-1 are very uncommon. Malignant peripheral nerve-sheath tumors (MPNST) are rare at this site, arising spontaneously or in the context of NF-1. This presentation discusses the clinical presentation, pathology, and management of these tumors, which usually occur in young adults. MPNST are intermediate or high-grade sarcomas with a high risk of local and distant spread. Approximately 50% of MPNST arise in patients with NF-1, and therefore these patients should be thoroughly investigated for any new symptoms or masses. MPNST of the brachial plexus should be treated with an adequate wide local excision, with adjuvant high-dose radiotherapy pre- or postoperatively. The role of chemotherapy in the treatment of MPNST is not clearly defined, but it may have some benefit in salvaging treatment failures.

Epidemiological study of muscular disorders in Assiut, Egypt.

Few comprehensive epidemiological studies of the prevalence of muscle diseases have been undertaken, and none has been carried out in our locality. The present cross-sectional study was conducted in Assiut Governorate (Upper Egypt) to estimate the prevalence of different types of primary muscular disorder in 1997. The study involved 52,203 subjects, 15,617 (30%) from the rural community and 36,586 (70%) from the urban community. Patients were identified from a door-to-door survey, and all were subjected to a full clinical examination, with confirmation of the diagnosis through electrophysiological, and biochemical investigations. Histopathological studies were performed for the classification of muscular dystrophies. Forty patients with muscular disorders were identified, with a point prevalence of 76.6 per 100,000 in the total community with no significant differences between the rural and urban communities. The creatine kinase level was abnormally high (>225 IU/l) in 80% of the cases, increased in all patients with muscular dystrophy or myositis, in 88.8% of patients with systemic myopathy and 66.6% of patients with myotonia. None of the cases of myasthenia showed an increase in the creatine kinase level. The lifetime prevalence per 100,000 was 26.8 for muscular dystrophy, 11.49 for myotonia, 11.49 for myositis, 17.24 for systemic myopathy and 9.57 for myasthenia.

Tissue microarray of head and neck squamous carcinoma: validation of the methodology for the study of cutaneous fatty acid-binding protein, vascular endothelial growth factor, involucrin and Ki-67.

Tissue microarrays allow the simultaneous analysis of many tumours using small-diameter cores sampled from larger blocks of tissue, but may be limited by tumour heterogeneity. This study considers the validation of tissue microarray for the study of four molecules of interest as prognostic factors in head and neck squamous carcinoma, including a consideration of methods for assessing immunocytochemical scoring of microarrays. Tissue microarray blocks were constructed from 100 cases of head and neck squamous carcinoma, taking four cores from different areas of each tumour. Immunocytochemical labelling was performed for cutaneous fatty acid binding protein, involucrin, vascular endothelial growth factor and Ki-67. The extent and intensity of scoring was determined for each core and the degree of agreement determined for results from the assessment of two, three or four cores for each carcinoma. In a subset of 30 representative cases, the labelling in the tissue microarrays was compared with that in whole-tissue sections of the same carcinomas. An adequate sample of carcinoma was achieved in more than 90% of the 400 cores; unsuccessful results were attributed to uneven core alignment or to poor targeting of the tumour tissue in the donor blocks. The degree of agreement in the assessment of extent and intensity of labelling was moderate to good (weighted kappa, range 0.479-0.902) between whole-tissue sections and microarray sections depending on the antigen and the scoring system. Tissue microarray is a reliable tool to demonstrate cellular and molecular alterations in head and neck squamous carcinomas. We recommend using the mean results from four cores for biological studies, with analysis of categorical data based on quartile groups. Concordance with whole-tissue section data is reassuring, but data from microarrays need to be validated against clinical outcomes.

Matrix metalloproteinase expression is related to angiogenesis and histologic grade in spindle cell soft tissue neoplasms of the extremities.

We defined the immunocytochemical expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in benign soft tissue neoplasms, fibromatoses, and sarcomas, together with the activity of gelatinase MMPs and TIMPs measured by zymography and reverse zymography in a subset of cases. The most strongly expressed MMP in all tumors was MMP-1, with weaker expression of MMP-10, MMP-11, and MMP-14 in most tumors. Nuclear expression of MMP-1, MMP-8, and MMP-13 was an unusual feature. TIMP-2 was expressed in all tumors, with stronger expression in fibromatoses than in sarcomas. Fibromatoses and high-grade sarcomas showed greater MMP-1 expression than other groups, and endothelial MMP-2 expression was more extensive in sarcomas. Differences in MMP and TIMP expression might be linked to the biologic behavior of soft tissue neoplasms. The activation of endothelial MMP-2 linked to widespread MMP-14 expression provides a mechanism for sarcomas to modulate their matrix and facilitate angiogenesis.