Davide Lanfranco

Prognostic modeling of oral cancer by gene profiles and clinicopathological co-variables

Accurate staging and outcome prediction is a major problem in clinical management of oral cancer patients, hampering high precision treatment and adjuvant therapy planning. Here, we have built and validated multivariable models that integrate gene signatures with clinical and pathological variables to improve staging and survival prediction of patients with oral squamous cell carcinoma (OSCC). Gene expression profiles from 249 human papillomavirus (HPV)-negative OSCCs were explored to identify a 22-gene lymph node metastasis signature (LNMsig) and a 40-gene overall survival signature (OSsig). To facilitate future clinical implementation and increase performance, these signatures were transferred to quantitative polymerase chain reaction (qPCR) assays and validated in an independent cohort of 125 HPV-negative tumors. When applied in the clinically relevant subgroup of early-stage (cT1-2N0) OSCC, the LNMsig could prevent overtreatment in two-third of the patients. Additionally, the integration of RT-qPCR gene signatures with clinical and pathological variables provided accurate prognostic models for oral cancer, strongly outperforming TNM. Finally, the OSsig gene signature identified a subpopulation of patients, currently considered at low-risk for disease-related survival, who showed an unexpected poor prognosis. These well-validated models will assist in personalizing primary treatment with respect to neck dissection and adjuvant therapies.

Biomarkers in neomark European project for oral cancers

Oral cavity cancers are the seventh tumor by diffusion worldwide with more than 90 % being diagnosed as oral squamous cell carcinomas (OSCCs). According to the latest WHO statistics, OSCC accounts for 5 % of the cancer deaths worldwide, being the eighth more lethal cancer entity. Early identification of cancer relapses would have the potentiality to improve the disease control and the patient survival. NeoMark is a European co-funded research project (Seventh Framework Program, Information and Communication Technologies: EU-FP7-ICT-20072-22483-NeoMark) that has the objective to identify relevant biomarkers of OSCC recurrence. It integrates high-throughput gene expression analysis in tumor cells and IT-assisted imaging with traditional staging and follow-up protocols to improve the recurrence risk stratification and to obtain the earlier identification of locoregional relapses. The architecture of the project is based on the following key points: – Creation of a web application tool: a unified interface that helps the storage and management of all information – NeoMark database: the heterogeneous NeoMark data (demographics and risk factors; clinical, pathological, and immunohistochemical parameters; filtered and cleaned genomic and imaging data) are stored in a single database – the M.J.R. da Fonseca Link Consulting – Tecnologias De Informacao S.A., Lisbon, Portugal e-mail: manuel.fonseca@link.pt M. De Fazio STMicroelectronics, Agrate Brianza (MI), Italy e-mail: marco.de-fazio@st.com 730 T. Poli et al.

Exclusive periductal/pericystic growth pattern in a case of long-standing monophasic synovial sarcoma of the parotid gland.

Sir: Synovial sarcoma (SS) is a rare mesenchymal malignant neoplasm that affects the head and neck region in only 5% of cases. In this scenario, the parotid gland is an exceedingly uncommon anatomical site. A 37-year-old man was referred to our hospital because of recurrence of a slow-growing right parotid mass. His complex clinical history started in 1996, when a computed tomography scan showed an oval/rounded nodule of 50 mm (Figure 1A) that was considered to be consistent with a benign lesion. In 1998, in view of a slight increase in size, fine needle aspiration cytology was performed, and showed cellular debris and inflammatory elements. In 2009, owing to further tumour enlargement, our patient underwent partial parotidectomy when histopathological interpretation resulted in an incorrect diagnosis of a ‘complex ductal cyst’. In late 2011, this lesion recurred as a 60-mm multicystic nodule (Figure 1B), and total parotidectomy was carried out. The histopathology of both the partial and total parotidectomy specimens (Figure 1C–F) was characterized by multiple cystically dilated ducts located in a dense and collagen fibre background. These cysts were lined by ductal epithelium with oxyphilic metaplasia. Interestingly, a monomorphic mesenchymal cuff composed of spindle cells was detectable around and along the above-mentioned ductal structures. These cells, organized in irregular sheets, showed moderately hyperchromic nuclei and small nucleoli. There was no vascular/perineural space invasion or lymph node metastasis. On immunohistochemistry, the spindle-cell component was positive for vimentin (monoclonal, dilution 1:500; Neomarkers, Fremont, CA, USA), CD99 (monoclonal, 1:50; Neomarkers; Figure 1G), TLE-1 (polyclonal, 1:75; Santa Cruz Biotechnology, Santa Cruz, CA, USA; Figure 1H), and bcl-2 (monoclonal, 1:300; Dako, Glostrup, Denmark), weakly positive for smooth muscle actin (monoclonal, 1:500; Neomarkers), and negative for cytokeratin 34BE12 (monoclonal, 1:500; Dako), cytokeratin OSCAR (monoclonal, 1:40; Covance, Princeton, NJ, USA), cytokeratin AE1/AE3 (monoclonal, 1:500; Dako), epithelial membrane antigen (monoclonal, 1:1000; Dako), S100 (monoclonal, 1:200; Neomarkers), CD10 (monoclonal, 1:50; Novocastra, Newcastle, UK), CD34 (monoclonal, 1:500; Neomarkers), CD117 (polyclonal, 1:100; Dako), and desmin (monoclonal, 1:100; Dako). The MIB-1 (monoclonal, 1:100; Dako) proliferative index was ~5%. A fluorescence in-situ hybridization (FISH) analysis was carried out with a Vysis SS18 Break Apart Probe Kit (Abbott Molecular, Des Plaines, IL, USA), which detected a typical SS translocation t(X;18) (SYT;SSX) only in the spindle cells (Figure 1I), and not in the oxyphilic epithelium (Figure 1L). On these bases, a diagnosis of monophasic SS with a periductal/cystic pattern of infiltration was made. Our review of the literature identified only seven biopsy-proven cases of SS occurring in the parotid gland. There were two males (29%) and five females (71%) aged 15–72 years (median value 35 years). Symptoms had lasted for 2–120 months (median value 24 months) before diagnosis, with the main signs/complaints being local swelling (seven cases, 100%), facial pain (two cases, 29%), headaches