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BACKGROUND: . At present, the prognostic prediction in advanced oral cavity squamous cell carcinoma (OCSCC) is based on the tumor-node-metastasis (TNM) staging system, and the most used imaging modality in these patients is magnetic resonance image (MRI). With the aim to improve the prediction, we developed an MRI-based radiomic signature as a prognostic marker for overall survival (OS) in OCSCC patients and compared it with published gene expression signatures for prognosis of OS in head and neck cancer patients, replicated herein on our OCSCC dataset.METHODS: For each patient, 1072 radiomic features were extracted from T1 and T2-weighted MRI (T1w and T2w). Features selection was performed, and an optimal set of five of them was used to fit a Cox proportional hazard regression model for OS. The radiomic signature was developed on a multi-centric locally advanced OCSCC retrospective dataset (n = 123) and validated on a prospective cohort (n = 108).RESULTS: The performance of the signature was evaluated in terms of C-index (0.68 (IQR 0.66-0.70)), hazard ratio (HR 2.64 (95% CI 1.62-4.31)), and high/low risk group stratification (log-rank p CONCLUSIONS: Overall, the present study suggests that MRI signatures, containing non-invasive and cost-effective remarkable information, could be exploited as prognostic tools.

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Contains fulltext : 281792.pdf (Publisher’s version ) (Open Access) Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.

Salvage surgery (SS) in head and neck cancer is considered a last resort treatment after failure of organ preservation treatments. It offers challenges to the patients and the surgeon. The outcome of SS is often uncertain in terms of survival and quality of life. This paper offers an overview of evolution in SS, tumor and patient factors to be considered, challenges in reconstructive surgery, complications of SS and the changing landscape with regard to increasing incidence of human papillomavirus positive tumours, the role of transoral robotic surgery, the importance of multidisciplinary management and shared decision making.

Funding information: Dutch Cancer Society (KWF- Alpe d'Huzes); Medical Faculty Ljubljana, Department of Family Medicine; Slovenian Research Agency (Young Researcher Program). Background: Patients with head and neck cancer (HNC) are vulnerable to fear of cancer recurrence (FCR) and psychiatric morbidity. We investigated the prevalence of high FCR and demographic, clinical, psychological, and psychiatric factors associated with high FCR prior to the start of the treatment. Methods: In a cross-sectional substudy of the large ongoing prospective NET-QUBIC study questionnaires and psychiatric interviews of 216 patients newly diagnosed with HNC were analyzed. Results: High FCR was observed in 52.8% of patients and among those 21.1% also had a lifetime history of selected anxiety or major depressive disorder. FCR was not related to any clinical characteristics; however, younger age, higher anxiety symptoms, introversion, greater needs for support regarding sexuality, and being an exsmoker were significantly associated with higher FCR. Conclusion: Factors associated with high FCR provide us with a better conceptual understanding of FCR in patients newly diagnosed with HNC. Publisher PDF

Background\ud \ud The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy.\ud \ud Methods\ud \ud We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of

The article as originally published contained errors in Figure 3. The direction of the arrows associated with the labels for p53 and RB were incorrect. This has now been corrected in all versions of the article.

Over the last three decades, it has become clear that infection with high-risk human papillomavirus (HPV) is etiologically linked to the development of head and neck squamous cell carcinomas, particularly those carcinomas that arise in the oropharyngeal region.

Concurrent chemoradiation is considered the golden standard in the treatment of locally advanced OPC. However, given the very high survival rates in favorable HPV-positive OPC and the high rates of acute and late treatment-related side effects, de-escalation strategies have to be considered. In this chapter, the potential benefit of a number of de-escalation strategies is described, including of replacement of concurrent chemotherapy by cetuximab, radiation dose de-escalation based on response to induction chemotherapy, radiotherapy alone without systemic treatment, and limiting elective nodal target volumes for radiation. In addition to de-escalation, modern radiation technologies like protons will offer increasing opportunities to decrease the dose to normal tissues in order to prevent radiation-induced toxicities. Initial analysis showed that radiation dose de-escalation based on response to induction chemotherapy in combination with intensity-modulated proton therapy (IMPT) has the highest potential to decrease acute and late toxicities.

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage, and despite intensive treatment prognosis remains poor. Accurate staging and tumor delineation are essential for determination of a personalized treatment strategy. Molecular imaging with radionuclides or fluorescent probes allows visualization of tumor biology in vivo. Positron emission tomography (PET) imaging gives whole body information with low resolution whereas optical molecular imaging has a high resolution but limited penetration and limited field of view. Therefore, PET imaging might improve staging and radiotherapy planning and optical imaging is of interest for early detection and guidance of surgical resection in HNSCC. In this chapter we describe how these techniques can be used to study the presence and distribution of specific tumor characteristics and tumor delivery of drugs. In addition, the current role of 18F-fluorodeoxyglucose (18F-FDG) PET is addressed, and non-FDG PET tracers including tracers for hypoxia and epidermal growth factor receptor (EGFR) imaging are discussed. We describe development of EGFR imaging with fluorescence and address preclinical imaging results in HNSCC models for other molecular targets, including integrin αvβ3. Adequately powered clinical trials are needed to assess the added value of molecular imaging before implementation, and standardization of techniques and endpoints is essential.

BACKGROUND: Information on posttraumatic growth (PTG) among head and neck cancer (HNC) survivors with a high level of distress is limited. The aim of this cross-sectional study was to investigate the occurrence of PTG among distressed HNC survivors and its association with anxiety, depressive, nicotine, and alcohol use disorders and health-related quality of life.METHODS: Seventy-four HNC survivors with psychological distress (Hospital Anxiety and Depression Scale (HADS) anxiety > 7 and/or HADS depression > 7) completed the Posttraumatic Growth Inventory, which comprises five subscales: relating to others, new possibilities, personal strength, spiritual change, and appreciation of life, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Anxiety, depressive, nicotine, and alcohol use disorders were measured using the Composite International Diagnostic Interview.RESULTS: Moderate to high Posttraumatic Growth Inventory (PTGI) scores occurred in 10% of the HNC survivors with distress. The mean total PTGI score was 30.8 (SD = 19.7), with the highest mean score on the subscale relating to others. A multivariate regression model consisting of tumor stage, anxiety disorder, alcohol use disorder, and social functioning predicted total PTGI score best (F(4, 64) = 7.565, p CONCLUSIONS: The presence of PTG in this population of distressed HNC survivors was low. PTG occurred most in the domain of relating to others. Among distressed HNC survivors, higher PTG was associated with lower tumor stage, absence of an anxiety disorder, absence of an alcohol use disorder, and better social functioning. Copyright © 2016 John Wiley & Sons, Ltd.

Background Sentinel node biopsy (SNB) in head and neck cancer is recently introduced as the staging technique of oral squamous cell carcinoma. We report the results of SNB in patients diagnosed with a T1-T2 oral squamous cell carcinoma and clinically negative (N0) neck in a single center. Methods A retrospective analysis of 90 previously untreated patients who underwent SNB between 2007 and 2012 was performed. The SNB procedure consisted of preoperatively performed lymphoscintigraphy, intraoperative detection using blue dye, and gamma probe guidance and histopathologic examination including step-serial sectioning (SSS) and immunohistochemical (IHC) staining. A positive SNB was followed by neck dissection, whereas regular follow-up with ultrasound-guided fine-needle aspiration cytology (FNAC) was done in case of a negative SNB. Results The lymphoscintigraphic identification rate was 98% (88 of 90 patients) and the surgical detection rate was 99% (87 of 88 patients). The upstaging rate was 30%. Sensitivity of SNB was 93% and the negative predictive value was 97%. The median follow-up was 18 months (range, 2-62 months). Overall survival (OS) and disease-free survival (DFS) for SNB negative were 100% and 84% and for SNB positive patients 73% and 88%, respectively. Conclusion SNB is a reliable diagnostic staging technique for the clinically negative neck in patients with early-stage (T1-T2, cN0) oral squamous cell carcinoma.

Background: Although many cancer survivors could benefit from supportive care, they often do not utilize such services. Previous studies have shown that patient-reported outcomes (PROs) could be a solution to meet cancer survivors’ needs, for example through an eHealth application that monitors quality of life and provides personalized advice and supportive care options. In order to develop an effective application that can successfully be implemented in current health care, it is important to include health care professionals in the development process. Objective: The aim of this study was to investigate health care professionals’ perspectives toward follow-up care and an eHealth application, OncoKompas, in follow-up cancer care that monitors quality of life via PROs, followed by automatically generated tailored feedback and personalized advice on supportive care. Methods: Health care professionals involved in head and neck cancer care (N=11) were interviewed on current follow-up care and the anticipated value of the proposed eHealth application (Step 1). A prototype of the eHealth application, OncoKompas, was developed (Step 2). Cognitive walkthroughs were conducted among health care professionals (N=21) to investigate perceived usability (Step 3). Interviews were recorded, transcribed verbatim, and analyzed by 2 coders. Results: Health care professionals indicated several barriers in current follow-up care including difficulties in detecting symptoms, patients’ perceived need for supportive care, and a lack of time to encourage survivors to obtain supportive care. Health care professionals expected the eHealth application to be of added value. The cognitive walkthroughs demonstrated that health care professionals emphasized the importance of tailoring care. They considered the navigation structure of OncoKompas to be complex. Health care professionals differed in their opinion toward the best strategy to implement the application in clinical practice but indicated that it should be incorporated in the HNC cancer care pathway to ensure all survivors would benefit. Conclusions: Health care professionals experienced several barriers in directing patients to supportive care. They were positive toward the development and implementation of an eHealth application and expected it could support survivors in obtaining supportive care tailored to their needs. The cognitive walkthroughs revealed several points for optimizing the application prototype and developing an efficient implementation strategy. Including health care professionals in an early phase of a participatory design approach is valuable in developing an eHealth application and an implementation strategy meeting stakeholders’ needs. [J Med Internet Res 2015;17(10):e235]

Diffusion-weighted MRI (DW-MRI) has potential to predict chemoradiotherapy (CRT) response in head and neck squamous cell carcinoma (HNSCC) and is generally performed using echo-planar imaging (EPI). However, EPI-DWI is susceptible to geometric distortions. Half-fourier acquisition single-shot turbo spin-echo (HASTE)-DWI may be an alternative. This prospective pilot study evaluates the potential predictive value of EPI- and HASTE-DWI and 18F-fluorodeoxyglucose PET-CT (18F-FDG-PET-CT) early during CRT for locoregional outcome in HNSCC.Eight patients with advanced HNSCC (7 primary tumors and 25 nodal metastases) scheduled for CRT, underwent DW-MRI (using both EPI- and HASTE-DWI) and 18F-FDG-PET(-CT) pretreatment, early during treatment and three months after treatment. Median follow-up time was 38 months.No local recurrences were detected during follow-up. Median Apparent Diffusion Coefficient (ADC)EPI-values in primary tumors increased from 77×10(-5) mm(2)/s pretreatment, to 113×10(-5) mm(2)/s during treatment (P=0.02), whereas ADCHASTE did not increase (74 and 74 mm(2)/s, respectively). Two regional recurrences were diagnosed. During treatment, ADCEPI tended to be higher for patients with regional control [(117.3±12.1)×10(-5) mm(2)/s] than for patients with a recurrence [(98.0±4.2)×10(-5) mm(2)/s]. This difference was not seen with ADCHASTE. No correlations between ΔADCEPI and ΔSUV (Standardized Uptake Value) were found in the primary tumor or nodal metastases.HASTE-DWI seems to be inadequate in early CRT response prediction, compared to EPI-DWI which has potential to predict locoregional outcome. EPI-DWI and 18F-FDG-PET-CT potentially provide independent information in the early response to treatment, since no correlations were found between ΔADCEPI and ΔSUV.

The extra domain B of fibronectin (ED-B) is a marker of tumor angiogenesis. The human monoclonal antibody (mAb) L19-SIP (∼80 kDa; SIP is "small immunoprotein") has been selected for targeting of ED-B. The aim of this study was to evaluate the potential of radioimmunotherapy (RIT) with L19-SIP, either alone or in combination with cetuximab, for treatment of head and neck squamous cell carcinoma (HNSCC). Combination with cetuximab was considered because this anti-EGFR (epidermal growth factor receptor) mAb has proven value for the treatment of HNSCC. Methods: HNSCC xenograft lines FaDu and HNX-OE were evaluated for ED-B and EGFR expression. L19-SIP was radiolabeled with 2 candidate radionuclides for RIT, 177Lu and 131I (or 125I as substitute). The biodistribution of coinjected 177Lu-L19-SIP and 125I-L19-SIP was assessed in FaDu-bearing nude mice, whereas 131I-L19-SIP was evaluated in both xenograft lines. After labeling with high-dose 131I (623-789 MBq/mg), the maximum tolerated dose (MTD) was assessed. The efficacy of RIT with injected 131I-L19-SIP, either alone or in combination with unlabeled cetuximab (1 mg 2 times a week intraperitoneally for 4 wk), was evaluated in both xenograft lines. Results: Xenograft lines expressed both antigens, with similar EGFR expression and the highest ED-B expression in FaDu. Radioiodinated L19-SIP performed better than 177Lu-L19-SIP and was further exploited. The biodistribution of 131I-L19-SIP was most favorable in FaDu-bearing mice, with tumor uptake values at 24, 48, and 72 h after injection of 8.± 6 1.6, 5.8 ± 0.4, and 3.4 ± 0.2 %ID/g (%ID/g is percentage injected dose per gram of tissue), respectively, and ratios of tumor to normal tissues that gradually increased in time, such as for blood from 4.4 ± 1.8 at 24 h to 21.4 ± 1.7 at 72 h, after injection. RIT at the MTD level of 74 MBq caused significant tumor growth delay and improved survival in both lines. Although FaDu was most sensitive for RIT, with size reduction of all tumors, HNX-OE was most sensitive for treatment with cetuximab. The best survival and cure rates were obtained, however, when RIT and cetuximab were combined. Conclusion: RIT with 131I-L19-SIP appeared efficacious in HNSCC xenografts. The efficacy of RIT was enhanced by combination with cetuximab, without increase of toxicity.

Purpose. Examination of the potential of electroporation therapy (EPT) in a patient with metastatic soft tissue sarcoma. Patient. A 24-year-old male who underwent extensive resection and postoperative radiotherapy for a malignant peripheral nerve sheath tumor in the right infratemporal fossa with intracranial extension and invasion of the maxillary sinus and mandible had a recurrence in the scar of his craniotomy for which he was initially treated with doxorubicin. After discontinuation of doxorubicin he developed a metastatic mass at the same site for which he was treated with electroporation therapy. Method. The subcutaneous metastasis was infiltrated with bleomycin and electroporated. Results. Gradually the tumor became increasingly necrotic and demarcated from surrounding tissue. After 10 weeks no tumor was seen anymore. The wound healed secondarily. Discussion. Intralesional bleomycin followed by EPT is potentially effective, well tolerated, and easy to perform in well accessible soft tissue sarcoma sites.

Immuno-PET as a scouting procedure before radioimmunotherapy (RIT) aims at confirming tumor targeting and accurately estimating radiation dose delivery to both tumor and normal tissues and might therefore be of value for selection of patient candidates for RIT. A prerequisite for this approach is that PET radioimmunoconjugates and RIT radioimmunoconjugates must show a similar biodistribution. In the present study, we evaluated the potential of the long-lived positron emitter 89Zr to predict biodistribution of the residualizing therapeutic radiometals 88Y (as a substitute for 90Y) and 177Lu when labeled to the monoclonal antibody (mAb) cetuximab via different types of chelates. Cetuximab was selected as a model mAb because it abundantly internalizes after binding to the epidermal growth factor receptor. Methods: Cetuximab was labeled with 89Zr using succinylated desferrioxamine B (N-sucDf). The chelates p-benzyl isothiocyanate-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (p-SCN-Bz-DOTA) and p-isothiocyanatobenzyl diethylenetriaminepentaacetic acid (p-SCN-Bz-DTPA) were both used for radiolabeling with 88Y and 177Lu. For measurement of the in vitro stability of each of the 5 radioimmuno-conjugates, samples were incubated in freshly prepared human serum at 37°C up to 16 d. Biodistribution was assessed at 24, 48, 72, and 144 h after intraperitoneal coinjection of the PET and RIT conjugates in nude mice bearing the squamous cell carcinoma xenograft line A431. Results: Cetuximab premodification with N-sucDf, p-SCN-Bz-DOTA, or p-SCN-Bz-DTPA resulted in chelate-to-mAb molar ratios of about 1. After radiolabeling and purification, the radiochemical purity and immunoreactive fraction of the conjugates always exceeded 97% and 93%, respectively. All conjugates were stable in serum, showing a radioactivity release of less than 5% until day 7. From day 7 until day 16, an enhanced release was observed for the 89Zr-N-sucDf, 88Y-p-SCN-Bz-DTPA, and 177Lu-p-SCN-Bz-DTPA conjugates. The coinjected PET and RIT conjugates showed similar biodistributions, except for the thighbone and sternum. For example, the 89Zr-N-sucDf conjugate showed a 2.0-2.5 times higher radioactivity accretion in the thighbone than did the RIT conjugates at 72 h after injection. Conclusion: In view of the advantages of PET over SPECT, 89Zr-immuno-PET is a promising modality for in vivo scouting of 90Y- and 177Lu-labeled mAbs, although care should be taken when estimating bone marrow doses.

Immuno-PET as a scouting procedure before radioimmunotherapy (RIT) aims at confirming tumor targeting and accurately estimating radiation dose delivery to both tumor and normal tissues and might therefore be of value for selection of patient candidates for RIT. A prerequisite for this approach is that PET radioimmunoconjugates and RIT radioimmunoconjugates must show a similar biodistribution. In the present study, we evaluated the potential of the long-lived positron emitter 89Zr to predict biodistribution of the residualizing therapeutic radiometals 88Y (as a substitute for 90Y) and 177Lu when labeled to the monoclonal antibody (mAb) cetuximab via different types of chelates. Cetuximab was selected as a model mAb because it abundantly internalizes after binding to the epidermal growth factor receptor. Methods: Cetuximab was labeled with 89Zr using succinylated desferrioxamine B (N-sucDf). The chelates p-benzyl isothiocyanate-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (p-SCN-Bz-DOTA) and p-isothiocyanatobenzyl diethylenetriaminepentaacetic acid (p-SCN-Bz-DTPA) were both used for radiolabeling with 88Y and 177Lu. For measurement of the in vitro stability of each of the 5 radioimmuno-conjugates, samples were incubated in freshly prepared human serum at 37°C up to 16 d. Biodistribution was assessed at 24, 48, 72, and 144 h after intraperitoneal coinjection of the PET and RIT conjugates in nude mice bearing the squamous cell carcinoma xenograft line A431. Results: Cetuximab premodification with N-sucDf, p-SCN-Bz-DOTA, or p-SCN-Bz-DTPA resulted in chelate-to-mAb molar ratios of about 1. After radiolabeling and purification, the radiochemical purity and immunoreactive fraction of the conjugates always exceeded 97% and 93%, respectively. All conjugates were stable in serum, showing a radioactivity release of less than 5% until day 7. From day 7 until day 16, an enhanced release was observed for the 89Zr-N-sucDf, 88Y-p-SCN-Bz-DTPA, and 177Lu-p-SCN-Bz-DTPA conjugates. The coinjected PET and RIT conjugates showed similar biodistributions, except for the thighbone and sternum. For example, the 89Zr-N-sucDf conjugate showed a 2.0-2.5 times higher radioactivity accretion in the thighbone than did the RIT conjugates at 72 h after injection. Conclusion: In view of the advantages of PET over SPECT, 89Zr-immuno-PET is a promising modality for in vivo scouting of 90Y- and 177Lu-labeled mAbs, although care should be taken when estimating bone marrow doses.

Based on recent genetic studies, we propose a progression model for the development of oral squamous cell carcinoma. In the initial phase, a stem cell acquires a genetic alteration; subsequently a patch is formed, a clonal unit consisting of the stem cell with its daughter cells that all share the DNA alteration. The next critical step is the conversion of a patch into an expanding field as a result of additional genetic alterations. This mucosal field replaces the normal epithelium and in the oral cavity such fields have been detected with dimensions of over 7 cm in diameter. Sometimes these fields are visible as leukoplakia. Ultimately, clonal selection leads to the development of carcinoma within this contiguous field of pre-neoplastic cells. An important clinical implication of this model is that fields often remain after surgery of the primary tumor and may lead to new cancers, presently designated by clinicians as second primary tumors or local recurrences.

PURPOSE: Approximately 10-30% of surgically treated head and neck cancer patients develop local recurrences while the resection margins are histologically tumor free. These recurrences may arise from cancer cells left behind but not detected by the pathologist, or they may develop from precursor lesions adjacent to the tumor that were not completely resected. We have investigated whether TP53-mutated DNA in the surgical margins is suitable to identify patients with head and neck squamous cell carcinoma at risk for local and locoregional recurrence. EXPERIMENTAL DESIGN: In a prospective cohort study of 76 patients with histologically tumor-free margins, the presence of TP53-mutated DNA was determined in the surgical margins using the phage plaque assay and correlated to clinical outcome. Immunostaining of the molecular-positive margins for mutated p53 protein was used to identify whether unresected precursor lesions or residual tumor cells were left behind. RESULTS: The absence of TP53-mutated DNA in surgical margins was significantly associated with remaining free of local and locoregional recurrence (P = 0.027 and P = 0.028, respectively). Moreover, the presence of TP53-mutated DNA in the surgical margins was an independent prognosticator for locoregional recurrence (relative risk = 7.1; P = 0.021; 95% confidence interval, 0.9-56). In 20% of the cases, the presence of TP53-mutated DNA in the surgical margins was found to be related to the presence of tumor-related precursor lesions. CONCLUSIONS: This study shows the value of TP53-mutated DNA as a molecular marker to predict locally recurrent head and neck squamous cell carcinoma. The observation that all patients who were negative for TP53-mutated DNA in the surgical margins remained free of local recurrence raises hope that molecular analysis of histologically tumor-free surgical margins can be exploited to decide on postoperative radiotherapy. Furthermore, our data provide evidence that local recurrences originate mainly from tumor cells left behind but also originate, in part, from unresected precursor lesions

The concept of "field cancerization" was first introduced by Slaughter et el. [D. P, Slaughter et al., Cancer (Phila.), 6: 963-968, 1953] in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. Organ systems in which field cancerization has been described since then are: head and neck (oral cavity, oropharynx, and larynx), lung, vulva, esophagus, cervix, breast, skin, colon, and bladder. Recent molecular findings support the carcinogenesis model in which the development of a field with genetically altered cells plays a central role. In the initial phase, a stem cell acquires genetic alterations and forms a "patch," a clonal unit of altered daughter cells. These patches can be recognized on the basis of mutations in TP53, and have been reported for head and neck, lung, skin, and breast cancer. The conversion of a patch into an expanding field is the next logical and critical step in epithelial carcinogenesis. Additional genetic alterations are required for this step, and by virtue of its growth advantage, a proliferating field gradually displaces the normal mucosa. In the mucosa of the head and neck, as well as the esophagus, such fields have been detected with dimensions of >7 cm in diameter, whereas they are usually not detected by routine diagnostic techniques. Ultimately, clonal divergence leads to the development of one or more tumors within a contiguous field of preneoplastic cells. An important clinical implication is that fields often remain after surgery of the primary tumor and may lead to new cancers, designated presently by clinicians as "a second primary tumor" or "local recurrence," depending on the exact site and time interval. In conclusion, the development of an expanding preneoplastic field appears to be a critical step in epithelial carcinogenesis with important clinical consequences. Diagnosis and treatment of epithelial cancers should not only be focused on the tumor but also on the field from which it developed.

The TNM-classification of the UICC is used for staging malignant tumours worldwide. From 2003 the new revised sixth edition must be used. In comparison with the fifth edition there are some general and some head and neck carcinoma specific alterations. Some designations are introduced if sentinel lymph node procedure or immunohistochemistry or molecular methods have been used. In the revised version some definitions for advanced tumour stages at several head and neck sites are changed. In the new classification of the primary tumour the terms erosion and invasion of cartilage or bone are used. At most head and neck sites T4 is divided in T4a and T4b.

Purpose: Staging of the clinically N0 neck in patients with head and neck squamous cell carcinoma (HNSCC) using ultrasound-guided, fine needle aspiration cytology (USgFNAC) has a false-negative rate of ∼ 20% that might be caused by inaccurate cytology. Molecular analysis of aspirate residues might reduce the false-negative rate, and we therefore set up a quantitative reverse transcription-PCR (Q-RT-PCR) assay based on TaqMan technology using the squamous cell-specific antigen E48 (Ly-6D) as molecular marker. Experimental design: The detection limit of the assay was determined in reconstruction experiments. The sensitivity of the assay was tested on cytological tumor-positive aspirate residues and the specificity on lymph node aspirate residues of noncancer controls. Subsequently, 235 lymph node aspirate residues of 64 HNSCC patients staged with USgFNAC were examined for the presence of E48 mRNA. E48 Q-RT-PCR results of the aspirated lymph nodes were compared with cytology and clinical outcome. Results: The detection limit of E48 Q-RT-PCR was a single tumor cell in a background of 106 peripheral blood mononuclear cells. From the 41 aspirates that were not evaluable at cytology, 24 (59%) could be diagnosed with E48 Q-RT-PCR. In the 191 aspirates that were tumor negative or not evaluable at cytology, 8 samples from 6 patients were E48 positive. These results were confirmed by histology or clinical outcome in 3 of 6 patients. E48 Q-RT-PCR showed an increase in sensitivity from 56 to 67% and an increase in frequency of reached diagnosis from 97 to 100% compared with cytology. The specificity decreased from 100 to 92%. Conclusions: Real-time E48 Q-RT-PCR is an accurate technique for squamous cell detection in lymph node aspirates of HNSCC patients. The assay shows an increase in sensitivity and frequency of reached diagnosis compared with cytology. The test could be implemented routinely in USgFNAC to diagnose cases for which cytological examination is not conclusive.

Adequate management of the clinically negative neck is vital and should be balanced between over and undertreatment. Compared to clinical examination ultrasound-guided fine-needle aspiration cytology (USgFNAC) at initial staging can reduce the risk of occult metastases for T1-T2 squamous cell carcinoma of the oral cavity or oropharynx considerably to 20%, which justifies local excision of the tumour and a wait-and-see policy for the neck. SN identification and aspiration did not decrease the false-negative rate, and we have therefore abandoned its use in this setting. Using USgFNAC for follow-up enabled early detection of a significant percentage of neck failures and a high salvage rate with therapeutic neck dissection of 80%. Detecting subclinical neck metastases continues to challenge clinicians and debate continues.

The favoured method of reconstruction for large head and neck defects after resection for cancer is microvascular free flaps. Success rates in excess of 95% can be achieved in major centers. Especially pharyngeal defects are very challenging to reconstruct functionally. For the major subsites within the pharynx we describe our preferred method, mainly based on the application of the thin pliable radial forearm flap. However, in some instances a bulky flap, such as the rectus abdominis flap is needed. For reconstruction of the pharyngo-esophagus the tubed forearm flap is currently most often used. Functional results and quality of life are very acceptable to good after these extensive procedures. Harvesting of the radial forearm flap yields mild but distinct morbidity and warrants addressing.

Positron emission tomography (PET) is a relative new diagnostic imaging technique. In patients tumour tissue can be visualized using PET camera after intravenous injection of fluor-18-deoxy-glucose (FDG). In patients with head and neck squamous cell carcinoma FDG-PET seems to be especially suitable to find an occult primary tumour in patients with a cervical lymph node metastasis of an unknown primary tumour, to screen for distant metastases and second primary tumours and to detect a recurrent laryngeal carcinoma after radiotherapy. For these indications FDG-PET may play a role in the prevention of unnecessarily diagnostic examinations and treatments. The definitive value of FDG-PET for these indications is currently under further investigation. The role of FDG-PET for the detection of lymph node metastases and prediction and monitoring of response on radiotherapy and chemotherapy is yet unclear. Developments of new techniques like fusion of PET with CT and MRI, the use of positron emitter labelled monoclonal antibodies and new tracers are in progress.