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Background: Addition of neoadjuvant immune checkpoint inhibition to standard-of-care interventions for locally advanced oral cancer could improve clinical outcome., Methods: In this study, 16 evaluable patients with stage III/IV oral cancer were treated with one dose of 480 mg nivolumab 3 weeks prior to surgery. Primary objectives were safety, feasibility, and suitability of programmed death receptor ligand-1 positron emission tomography (PD-L1 PET) as a biomarker for response. Imaging included 18 F-BMS-986192 (PD-L1) PET and 18 F-fluorodeoxyglucose (FDG) PET before and after nivolumab treatment. Secondary objectives included clinical and pathological response, and immune profiling of peripheral blood mononuclear cells (PBMCs) for response prediction. Baseline tumor biopsies and postnivolumab resection specimens were evaluated by histopathology., Results: Grade III or higher adverse events were not observed and treatment was not delayed in relation to nivolumab administration and other study procedures. Six patients (38%) had a pathological response, of whom three (19%) had a major (≥90%) pathological response (MPR). Tumor PD-L1 PET uptake (quantified using standard uptake value) was not statistically different in patients with or without MPR (median 5.3 vs 3.4). All major responders showed a significantly postnivolumab decreased signal on FDG PET. PBMC immune phenotyping showed higher levels of CD8 + T cell activation in MPR patients, evidenced by higher baseline expression levels of PD-1, TIGIT, IFNγ and lower levels of PD-L1., Conclusion: Together these data support that neoadjuvant treatment of advanced-stage oral cancers with nivolumab was safe and induced an MPR in a promising 19% of patients. Response was associated with decreased FDG PET uptake as well as activation status of peripheral T cell populations., Competing Interests: Competing interests: RvdV has received research funding from Genmab BV. TDdG is scientific advisor to Immunicum, GE Health, and Lava Therapeutics, holds stock from LAVA Therapeutics and received research funding from Idera Pharmaceuticals (now Aceragen). RHB received research grants from KWF Kankerbestrijding/Dutch Cancer Society, Cancer Center Amsterdam Foundation, ZonMW and NWO, Genmab BV and the Hanarth Foundation and is on the advisory board of Nanobiotix. He has a scientific collaboration with Orfenix BV and Qialix DoT. CRL received research grants from KWF Kankerbestrijding/Dutch Cancer Society, Cancer Center Amsterdam Foudation, Genmab BV, BMS and the Hanarth Foundation and is on the advisory board of Merck & Co. CWM-vdHvO received research grants from BMS, Boeringher Ingelheim, GSK, Pfizer and AstraZeneca and consulted for GE Health Care, Novartis and EliLilly. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowledged, and HPV-status is assessed routinely in clinical practice. Paradoxically, while the oral cavity seems the predilection site for productive HPV-infections, figures on HPV-attribution in oral cavity squamous cell carcinoma (OCSCC) differ widely, and prognostic impact is uncertain. Major obstacles are the lack of reproducible assays to detect HPV in nonoropharyngeal cancers, the relatively small cohorts studied and consequently the shortfall of convincing data. In our study, we used a validated, nucleic acid-based workflow to assess HPV-prevalence in a consecutive cohort of 1016 OCSCCs, and investigated its prognostic impact. In parallel, we analyzed p16-immunohistochemistry (p16-IHC) as surrogate marker for transforming HPV-infection and independent prognosticator. All OCSCC-patients diagnosed between 2008 and 2014 at two Dutch university medical centers were included (N = 1069). Formalin-fixed, paraffin-embedded (FFPE)-samples of 1016 OCSCCs could be retrieved. Punch biopsies were taken from the tumor area in the FFPE-blocks and tested for HPV. P16-IHC was performed on 580 OCSCCs, including all HPV-positive tumors. From 940 samples (92.5%), nucleic acids were of sufficient quality for HPV-testing. In total, 21 (2.2%) OCSCCs were HPV DNA-positive. All HPV DNA-positive tumors were E6 mRNA-positive and considered as true HPV-positive. There was no difference in survival between HPV-positive and HPV-negative OCSCCs. In total, 46 of 580 (7.9%) OCSCCs were p16-immunopositive, including all HPV-positive tumors. Survival was comparable in p16-positive and p16-negative OCSCCs. To conclude, HPV-prevalence is very low in OCSCC and neither HPV-status nor p16-status affects outcome. Based on these data, determining HPV-status in OCSCC seems irrelevant for clinical management., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Rationale: This study evaluates the lymphatic drainage patterns and determines the accuracy of the sentinel lymph node biopsy (SLNB) in patients diagnosed with a cT1-2N0 OSCC and a history of neck surgery or radiotherapy in three Dutch head and neck centers., Materials and Methods: Retrospective analysis of 53 cT1-2N0 OSCC patients, who underwent SLNB between 2007 and 2016, after a history of neck surgery or radiotherapy. Ten patients had previous treatment of the neck only contralateral from the current tumour. These ten patients were not used for the analysis of lymphatic drainage patterns. The 43 patients with previous ipsilateral or bilateral treatment of the neck had a history of ipsilateral SLN extirpation (n = 9; 21%), neck dissection (n = 16; 37%), radiotherapy (n = 10; 23%), or combined neck dissection and radiotherapy (n = 8; 19%)., Results: SLNs were detected in 45 patients, resulting in an identification rate of 85% (45/53). Three patients (7%) had at least one positive SLN. One patient (1/45; 2%) was diagnosed with regional recurrence during the follow-up after a negative SLNB (sensitivity 75%, negative predictive value 98%). The first SLN was detected in level I-III in 58% of the patients, unexpected drainage patterns were observed in 30% (first SLN level IV 9% and level V 5% and contralateral neck in well-lateralized tumours 16%). In 12% no lymphatic drainage pattern was visible., Conclusions: SLNB seems to be a reliable procedure for neck staging of cT1-2N0 OSCC patients with a previously treated neck. SLNB determines the individual lymphatic drainage patterns, enabling visualization of unexpected drainage pattern variability in 30% of these patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: To investigate if depth of invasion (DOI) can predict occult nodal disease in patients with cT1-2N0 (7th TNM) oral squamous cell carcinoma (OSCC) staged by sentinel lymph node biopsy (SLNB)., Methods: In 199 OSCC patients, DOI measurements and SLNB were performed., Results: Metastases were found in 64 of 199 patients (32%). Of these 64 patients, the mean DOI was 6.6 mm compared to 4.7 mm in patients without metastases (P = .003). The ROC-curve showed an area under the curve of 0.65 with a most optimal cutoff point of 3.4 mm DOI (sensitivity 83% and specificity 47%). Regional metastases were found in 15% of patients with DOI ≤ 3.4 mm., Conclusion: DOI seems to be a poor predictor for regional metastasis in patients with cT1-2N0 OSCC. Therefore, staging of the neck using SLNB in patients with early stage oral cancer should also be performed in tumors with limited DOI and probably in T3 (8th TNM) OSCC ≤4 cm diameter., (© 2019 The Authors. Head & Neck published by Wiley Periodicals, Inc.)

Head and neck squamous cell carcinoma (HNSCC) is typically regarded as a disease of elderly people. However, increasing numbers of patients worldwide with HNSCC at younger age (defined as <45 years old) have been reported in recent years. To assess geographical variations and trends worldwide in incidence of oral and oropharyngeal cancer in young patients, a systematic review was conducted in PubMed and Google scholar databases from 1975 to June 2016. Seventy-eight studies were selected for further study. Nineteen population-based studies on incidence rate were available from 13 countries, showing a prominent increase over time except for the Netherlands. A notable rise of oral (mobile) tongue cancer among white women and oropharyngeal cancer in white men was observed. Data suggest that cancer in young patients may be a distinct clinical entity and characterised by different aetiology and pathogenesis. Additionally, the relative proportion of oral and oropharyngeal cancer in young patients to total incidence revealed a significant difference between estimates from North America (5.5%) and both Africa (17.2%) and Middle East (14.5%). It is concluded that (i) a rising trend in oral and oropharynx cancers is observed in young patients worldwide; (ii) incidence studies should properly define outcomes in age cohorts and use a consensus cut-off for young patients; (iii) more population-based studies should be performed in non-Western regions to get accurate global measures of incidence for these cancers in young subpopulations and (iv) there is an urge to identify new aetiological factors in these young patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To explore the possibility of shortening the length of follow-up from 5 to 3 years in patients who have undergone curative treatment of an oral squamous cell carcinoma., Study Design: The medical records of 225 patients who had undergone initial curative treatment at the VU University Medical Center in Amsterdam, the Netherlands, between 2004 and 2009 were analyzed., Results: In 96 patients (42.7%) a secondary event occurred. Eighty-six percent of the secondary events were detected within 3 years. In the fourth and fifth years, 14% of the secondary events were found, consisting mainly of second primary tumors., Conclusions: Most secondary events occurred within the first 3 years of follow-up. Therefore, the case can be made for an altered regimen of follow-up beyond 3 years based on certain risk factors unique to the patient as well as the patient's ability to adequately report symptoms that may be associated with recurrent disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Oral squamous cell carcinoma (OSCC) may develop in young adults. In contrast to older patients, the well-known etiological factors, exposure to tobacco and alcohol, play a minor role in the carcinogenesis in this patient group. It has been suggested that an intrinsic susceptibility to environmental genotoxic exposures plays a role in the development of OSCC in these patients. The hypothesis was tested whether young OSCC patients have an increased sensitivity to induced chromosomal damage., Subjects and Methods: Fourteen OSCC patients with an average age of 32 years (range 20-42) were selected. Peripheral blood lymphocytes and skin fibroblasts of patients and 14 healthy controls were subjected to the chromosome breakage test with Mitomycin C. This test is routinely used to identify Fanconi anemia patients, who are well-known for their inherited high sensitivity to this type of DNA damage, but also for the high risk to develop OSCC. Human papilloma virus status of the carcinomas was also determined., Results: None of the 14 young patients with OSCC had an increased response in the MMC-chromosomal breakage test. All tumors tested negative for human papilloma virus., Conclusion: No evidence was obtained for the existence of a constitutional hypersensitivity to DNA chromosomal damage as a potential risk factor for OSCC in young adults., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

LOH at chromosome arms 3p, 9p, 11q, and 17p are well-established oncogenetic aberrations in oral precancerous lesions and promising biomarkers to monitor the development of oral cancer. Noninvasive LOH screening of brushed oral cells is a preferable method for precancer detection in patients at increased risk for head and neck squamous cell carcinoma (HNSCC), such as patients with Fanconi anemia. We determined the prevalence of LOH in brushed samples of the oral epithelium of 141 patients with Fanconi anemia and 144 aged subjects, and studied the association between LOH and HNSCC. LOH was present in 14 (9.9%) nontransplanted patients with Fanconi anemia, whereas LOH was not detected in a low-risk group (n = 50, >58 years, nonsmoking/nonalcohol history) and a group with somewhat increased HNSCC risk (n = 94, >58 years, heavy smoking/excessive alcohol use); Fisher exact test, P = 0.023 and P = 0.001, respectively. Most frequent genetic alteration was LOH at 9p. Age was a significant predictor of LOH (OR, 1.13, P = 0.001). Five patients with Fanconi anemia developed HNSCC during the study at a median age of 39.6 years (range, 24.8-53.7). LOH was significantly associated with HNSCC (Fisher exact test, P = 0.000). Unexpectedly, the LOH assay could not be used for transplanted patients with Fanconi anemia because donor DNA in brushed oral epithelium, most likely from donor leukocytes present in the oral cavity, disturbed the analysis. Noninvasive screening using a LOH assay on brushed samples of the oral epithelium has a promising outlook in patients with Fanconi anemia. However, assays need to be adapted in case of stem cell transplantation, because of contaminating donor DNA., (©2015 American Association for Cancer Research.)

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., (© 2014 Wiley Periodicals, Inc.)

Objectives: Results of the Dutch multi-institutional trial on sentinel lymph node (SLN) biopsy in oral cancer., Patients and Methods: Patients were consecutively enrolled from 4 institutions, with T1/T2 oral cancer and cN0 neck based on palpation and ultrasound guided fine needle aspiration cytology. Lymphatic mapping consisted of preoperative lymphoscintigraphy. For intraoperative SLN detection a gamma-probe was used and in some patients additional blue dye. SLN negative patients were carefully observed, SLN positive patients were treated by neck dissection, radiotherapy or a combination of both. Endpoints of the study were risk of occult lymp node metastases, neck control, accuracy, 5-year disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS)., Results: Twenty of 62 patients (32%) had positive SLNs. Macrometastases were found in 9 patients, micrometastases in 8, and isolated tumour cells in 3 patients. Median follow-up was 52.5 months. Of the 42 SLN negative patients, 5 developed a regional recurrence of whom 4 patients could be successfully salvaged. DFS, OS and DSS of SLN negative patients were 72.0%, 92.7% and 97.4%, and for SLN positive patients these numbers were 73.7%, 79.7%, 85.0%, respectively (DFS: p=0.916, OS: p=0.134, DSS: p=0.059, respectively). Neck control rate was 97% in SLN negative and 95% in SLN positive patients. Sensitivity was 80% and negative predictive value 88%., Conclusion: SLN biopsy is able to reduce the risk of occult lymph node metastases in T1/T2 oral cancer patients from 40% to 8%, and enables excellent control of the neck., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Incidence and survival trends of head and neck squamous cell carcinoma (HNSCC) are essential knowledge for guiding policy making and research., Methods: The total population of the Netherlands was studied covering 1989-2011. Two-and five-year survival and age-standardized incidence rates of HNSCC were assessed in relation to site, gender and age (15 years-of-age categories)., Results: We recorded a statistically significant increase of oral, oropharyngeal and hypopharyngeal carcinoma for males and females of all ages, varying from 0.6% (hypopharynx in males) to 2.7% (oropharynx in females) per year. The incidence of laryngeal carcinoma significantly decreased for males with 2.3% per year; for females the situation was stable. In young adults (below 45 years of age) the incidence figures were different: significant decreasing incidence trends were seen for both genders for carcinomas of the oropharynx, hypopharynx and larynx. Regarding oral carcinoma, no change was observed for the young patient group, but for subsites trends were divergent. Carcinoma of the floor or mouth decreased for both genders, but carcinoma of the tongue rose by a significant 2.8% per year for young males. Five-year survival trends for all ages showed no change for laryngeal carcinoma, a small improvement for oral and hypopharyngeal carcinoma, and a substantial and significant improvement of survival from 36% to 47% survival over the total period for oropharyngeal carcinoma., Conclusion: In the Netherlands for the last two decades, the incidence of oral, oropharyngeal and hypopharyngeal squamous cell carcinoma has increased and survival has improved. The incidence of laryngeal carcinoma has decreased in males, and remained unchanged in females; survival from laryngeal carcinoma has not changed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate long-term changes in health related quality of life (HRQOL) in oral/oropharyngeal cancer survivors and their need for and use of supportive care., Methods: Between 1999 and 2001, 80 advanced oral or oropharyngeal cancer patients treated with free-flap reconstruction and postoperative radiotherapy were included in a prospective study of whom 27 patients were long-term survivors (mean 9.2 years, range 8-11 years). The HRQOL of 26 patients (response rate 96%) was assessed with the EORTC QLQ-C30 and QLQ-H&N35 questionnaires at four points in time: pretreatment (baseline), and at 6 months, 12 months (short term) and 8-11 years (long-term) follow up. A study specific questionnaire was developed to evaluate the need for and use of supportive care (allied health services, peer contact, psychosocial care, and complementary care) and was completed at the period of treatment and at long-term follow up., Results: A number of HRQOL domains worsened significantly (p < 0.01) in the long-term: emotional functioning, social functioning, swallowing, speech, taste/smell, dry mouth, sticky saliva and coughing assessed by the mixed effects statistical model. At time of treatment, the need for supportive care was the highest for a dental hygienist (77%), a physical therapist (73%), a speech therapist (42%), a dietician (38%), and a special diet (62%). At long-term follow up, the need for supportive care was limited to a dental hygienist (46%) and a physical therapist (23%). Only small differences were observed between the perceived need for and actual use of supportive care., Conclusion: A range of HRQOL domains in head and neck cancer survivors were deteriorated in the long-term compared to baseline and to the first year after treatment. At time of treatment and less frequently at long-term follow up, patients reported needing and using a variety of supportive care services., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Unlabelled: With conventional imaging techniques such as planar lymphoscintigraphy and SPECT/CT, preoperative sentinel node (SN) identification can be difficult when the SN is near the primary tumor, as is the case in floor-of-mouth carcinomas. PET/CT lymphoscintigraphy may improve the detection and localization of such SNs., Methods: In this study, the clinical feasibility of PET/CT lymphoscintigraphy using (89)Zr-nanocolloidal albumin was evaluated in 5 oral cancer patients. PET/CT lymphoscintigraphy was performed after peritumoral injection of (89)Zr-nanocolloidal albumin. The routine SN procedure, including SPECT/CT using (99m)Tc-nanocolloidal albumin, was performed on the same patients 7-9 d after the injection of (89)Zr-nanocolloidal albumin., Results: Comparison of radiocolloid distribution on PET/CT and SPECT/CT showed identical drainage patterns. Moreover, PET/CT was able to identify additional foci near the primary tumor., Conclusion: This pilot PET/CT study on SN detection indicated that lymphoscintigraphy using (89)Zr-nanocolloidal albumin is feasible.

Objectives: Management of the clinically N0 neck in oral cancer patients remains controversial. We describe the outcome of patients with T1-T2 oral cancer and N0 neck based on ultrasound guided fine needle aspiration cytology (USgFNAC) who were treated by transoral excision and followed by a 'wait and scan' policy (W&S)., Patients and Methods: This retrospective analysis included 285 consecutive patients of whom 234 were followed by W&S and 51 underwent elective neck dissection (END). Survival rates were compared between groups and correction for confounding factors was performed., Results: Of W&S patients, the 5-year disease-specific (DSS) and overall survival (OS) were 94.2% and 81.6% respectively. During follow-up 72.2% remained free of lymph node metastases and 27.8% developed delayed metastases. W&S patients with delayed metastases had a 5-year DSS and OS of 80.0% and 62.8%, respectively. In patients with positive END these rates were 81.3% and 64.2%, respectively. Between the groups, survival rates were not significantly different. Of the W&S patients with delayed metastases, 90.6% needed adjuvant radiotherapy versus 55.0% of patients with positive END., Conclusion: With regard to survival, in patients with early stage oral cancer and cN0 neck a 'wait and scan' policy using strict USgFNAC surveillance is justified as survival is not negatively influenced. Using a 'wait and scan' follow-up strategy instead of elective neck treatment, unnecessary neck dissection and its accompanying morbidity can be avoided in 72.2% of patients. However, for the small proportion of patients with delayed metastases, more extensive treatment with adjuvant radiotherapy is needed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Current assessment of lymph node metastasis in patients with head and neck squamous cell carcinoma is not accurate enough to prevent overtreatment. The aim of this study was validation of a gene expression signature for distinguishing metastasizing (N+) from nonmetastasizing (N0) squamous cell carcinoma of the oral cavity (OSCC) and oropharynx (OPSCC) in a large multicenter cohort, using a diagnostic DNA microarray in a Clinical Laboratory Improvement Amendments/International Organization for Standardization-approved laboratory., Methods: A multigene signature, previously reported as predictive for the presence of lymph node metastases in OSCC and OPSCC, was first re-evaluated and trained on 94 samples using generic, whole-genome, DNA microarrays. Signature genes were then transferred to a dedicated diagnostic microarray using the same technology platform. Additional samples (n=222) were collected from all head and neck oncologic centers in the Netherlands and analyzed with the diagnostic microarray. Human papillomavirus status was determined by real-time quantitative polymerase chain reaction., Results: The negative predictive value (NPV) of the diagnostic signature on the entire validation cohort (n=222) was 72%. The signature performed well on the most relevant subset of early-stage (cT1-T2N0) OSCC (n=101), with an NPV of 89%., Conclusion: Combining current clinical assessment with the expression signature would decrease the rate of undetected nodal metastases from 28% to 11% in early-stage OSCC. This should be sufficient to enable clinicians to refrain from elective neck treatment. A new clinical decision model that incorporates the expression signature is therefore proposed for testing in a prospective study, which could substantially improve treatment for this group of patients.

Background: High rates of positive surgical margins are reported after a maxillectomy. A large part of tumors that are preoperatively considered "operable" can thus not be resected with tumor-free margins., Methods: This was a retrospective study on medical files of 69 patients that underwent maxillectomy as primary treatment for a squamous cell carcinoma., Results: More than one third (39%) of all resections performed is incomplete, with dorsal or dorsocranial-positive surgical margins in two thirds. Correlation of tumor extension on preoperative imaging to surgical margins status revealed that dorsal and cranial tumor extension were significant prognostic factors for tumor positive surgical margins (p = .006 and p = .031, respectively). Positive margins were associated with a 2-fold increased risk of death (hazard ratio, 2.4; 95% confidence interval, 1.2-4.9)., Conclusion: Cranial or dorsal tumor extension on preoperative imaging was a significant risk factor for positive surgical margins after maxillectomy with significant negative influence on overall survival., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: Various lymphoscintigraphic imaging protocols exist for sentinel node (SN) identification in early-stage oral cancer. This study aimed to evaluate the clinical value of performing additional late lymphoscintigraphic imaging., Methods: We retrospectively analysed early (directly following injection of 99mTc-Nanocoll) and late (2-4 h after injection) imaging results of 60 early-stage (T1-T2, cN0) oral cancer patients scheduled for SN procedure. Lymphoscintigraphic results of late imaging were categorized into: (a) no visualization of additional hotspots considered to be SNs; (b) additional hotspots visualized that are considered to be SNs and (c) hotspots visualized only during late imaging. Histopathological results of the harvested SNs were related to the corresponding hotspot., Results: In all patients (n=60) lymphoscintigraphy was able to visualize a hotspot that was identified as an SN. In 51/60 (85%) patients, early imaging was able to visualize at least one hotspot, whereas in 9/60 (15%) patients, mostly with oral cavity tumours other than mobile tongue and floor-of-mouth tumours, only late imaging was able to visualize hotspots. In 14/51 (27%) patients, late imaging resulted in additionally visualized hotspots marked as SNs, resulting in a more extensive surgical procedure. These additionally removed SNs appeared to be of no clinical relevance, as all SNs identified during early imaging correctly predicted whether the neck was positive or negative for cancer., Conclusion: Results of this study indicate that additional late lymphoscintigraphic imaging should be performed only in selected cases.

Background: In current practice, surgeons frequently deal with elderly patients who have severe medical comorbidities., Methods: We present our series of 18 consecutive patients with severe general comorbidities that received infrahyoid flap reconstruction. The results were compared with those of 16 consecutive patients in good general medical state receiving free radial forearm flap reconstruction during the same study period. We also describe an original method for tongue base reconstruction using the infrahyoid flap., Results: No total flap necrosis was experienced; successful separation between oral cavity/oropharyngeal contents and neck spaces was obtained in all patients with a low rate of general complications. No significant differences were found with regard to verbal intelligibility and diet scores between groups., Conclusions: Infrahyoid flap in high-risk cases represents a valid alternative to free radial forearm flap. We introduced a novel technical innovation for tongue base reconstruction using the infrahyoid flap with very encouraging results., (Copyright © 2011 Wiley Periodicals, Inc.)

In patients with early stage oral or oropharyngeal squamous cell carcinoma (OSCC) sentinel node biopsy (SNB) is a reliable method to detect occult disease in the neck. However, patients with a history of surgery or radiotherapy in the neck may have aberrant lymphatic drainage caused by disruption of lymphatic channels. Therefore, treatment of the same levels at risk as in the primary setting may not be appropriate. The aim of our prospective observational study was to evaluate the clinical application of SNB in previously treated OSCC. Between 2003 and 2010 twenty-two patients were included. Lymph node mapping consisted of preoperative lymphoscintigraphy, SPECT/CT, intraoperative use of gamma-probe and patent blue. Endpoints were the sentinel node (SN) detection rate, unexpected lymphatic drainage patterns, negative predictive value and regional tumor control. 4/22 (18%) Patients were previously treated only on the contralateral site. The SN detection rate was 100% and unexpected drainage was found in 1/4 patients. The other 18 patients had ipsi- or bilateral previous neck treatment and a SN detection rate of 83%. The upstaging rate was 7% and 67% had unexpected lymphatic drainage patterns. The median follow-up was 22 months. Regional tumor control and negative predictive value were 100%. SNB in previously treated OSCC patients is feasible. SN detection is reliable and regional tumor control after staging by SNB is excellent. Moreover, SNB renders an assessment of the individual lymphatic drainage pattern, compensating for a potential variability after previous treatment of the neck., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Investigation of applicability of neural network feature analysis of nasalance in speech to assess hypernasality in speech of patients treated for oral or oropharyngeal cancer., Patients and Methods: Speech recordings of 51 patients and of 18 control speakers were evaluated regarding hypernasality, articulation, intelligibility, and patient-reported speech outcome. Feature analysis of nasalance was performed on /a/, /i/, and /u/ and on the entire stretch of speech., Results: Nasalance distinguished significantly between patients and controls. Nasalance in /a/ and /i/ predicted best intelligibility, nasalance in /a/ predicted best articulation, and nasalance in /i/ and /u/ predicted best hypernasality., Conclusion: Feature analysis of nasalance in oral or oropharyngeal cancer patients is feasible; prediction of subjective parameters varies between moderate and poor.

Objectives: In this study we evaluated the possible epidemiologic changes of oral cancer patients in the Netherlands between the years 1980-1984 and 2000-2004. We specifically studied the differences in male-female ratio, age, TNM-stage, site distribution, and alcohol and tobacco use., Materials and Methods: Patients from the VU University Medical Center with an oral squamous cell carcinoma of the oral cavity registered in 1980-1984 (n=200), group 1, were compared to patients registered in 2000-2004 (n=184), group 2. Trends in prevalence, site distribution, TNM-stage, alcohol and tobacco use, age and gender were studied., Results: The male-female ratio has decreased from 1.8 to 1.2. There were no differences in age between the two groups of patients. The site distribution was similar in both groups. The most commonly involved sites were the tongue and the floor of mouth. In group 2 more patients were diagnosed with a T1 tumour. There were no differences in tobacco use between the two different groups. There were much more light drinkers (0-2 drinks per day) in group 2 than in group 1, whereas there were more heavy drinkers (>4 per day) in group 1 than in group 2 (p<0.001). This was observed in both male and female patients., Conclusion: In our study there were no significant differences between the patients registered in the years 1980-1984 and 2000-2004 regarding the mean age of the patients, site distribution and smoking habits. The male-female ratio has decreased. In the recent group more patients were staged T1N0 and there was a strong decrease of the patients who were heavy drinkers.

Oral leukoplakia is a potentially malignant disorder that will develop into oral cancer at an estimated rate of 1-2% per year. Aim of the present study is to assess the possible predictive value of DNA ploidy for malignant progression of oral leukoplakia. A cohort of 62 leukoplakia patients was studied and their biopsy was examined with standard histopathology and DNA image cytometry. Cox regression analysis was performed to establish the relationship between progression-free survival and the DNA ploidy status. During the follow-up time (median of 69 months) 13 patients developed an oral squamous cell carcinoma (OSCC). DNA aneuploidy was observed in 27 (44%) patients and was significantly associated with a shorter progression-free survival [Hazard ratio of 3.7, 95% confidence intervals (CI) of 1.1 and 13.0 and a p-value of 0.04]. Sensitivity and specificity scores were 54% and 60%, respectively. Aneuploidy was not correlated with dysplasia grading (chi-square analysis). DNA aneuploidy in oral leukoplakia is associated with an increased risk of progression to OSCC. However, for the individual leukoplakia patient, DNA ploidy status as single biomarker has limited value to predict progression to cancer., (Copyright © 2011. Published by Elsevier Ltd.)

Currently, selection of lymph nodes for ultrasound-guided-fine-needle-aspiration cytology (USgFNAC) in patients with HNSCC relies mainly on size of lymph nodes. This retrospective study was undertaken to assess the potential value of size, laterality, level and changes in size as criteria for selection of nodes that need to be aspirated during follow-up of patients. We aim to reduce the number of unnecessary aspirations being performed without decreasing accuracy of USgFNAC. Eighty-one patients with oral cavity carcinoma (OCC) were eligible for observation-policy regarding treatment of the neck and received transoral excision of OCC. Selection of nodes for fine-needle-aspiration-cytology (FNAC) was based on size criterion. Localization (side and level) and size of aspirated lymph nodes were scored. Data on treatment and follow-up were collected and analyzed to assess the value of the used criteria. During follow-up all 17 positive nodes were found, of which 16 were ipsilateral. Contralateral metastasis was found in a patient with ipsilateral metastasis and a tumor crossing the midline. Minimal axial diameter (MAD) of all positive nodes was larger than 5.0mm in level II or 4.0mm in other levels. Follow-up aspirations in patients with OCC performed in the neck by USgFNAC can be reduced by 56% without increasing false-negative lymph nodes if follow-up aspirations would only be performed on the ipsilateral neck in lymph nodes with a MAD of 5mm in level II and 4mm in other levels or larger and in lymph nodes with rapid change of diameter., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background and Purpose: The relation between health-related quality of life (HRQOL) and survival was investigated at baseline and 6 months in 80 patients with advanced oral or oropharyngeal cancer after microvascular reconstructive surgery and (almost all) adjuvant radiotherapy., Materials and Methods: Multivariate Cox regression analyses of overall and disease-specific survival were performed including sociodemographic (age, gender, marital status, comorbidity), and clinical (tumor stage and site, radical surgical, metastasis, radiotherapy) parameters, and HRQOL (EORTC QLQ-C30 global quality of life scale)., Results: Before treatment, younger age and having a partner were predictors of disease-specific survival; younger age predicted overall survival. At 6 months post-treatment, disease-specific and overall survival was predicted by (deterioration of) global quality of life solely. Global health-related quality of life after treatment was mainly influenced by emotional functioning., Conclusion: Deterioration of global quality of life after treatment is an independent predictor of survival in patients with advanced oral or oropharyngeal cancer., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The aim of this study was to evaluate feasibility, reliability, validity of the SWAL-QOL (a questionnaire on swallowing problems in daily life), and to define sample size calculations and a clinically relevant cut-off score. One hundred and two patients were treated for cancer of the oral cavity or pharynx and 111 healthy subjects completed the SWAL-QOL and the EORTC H and N35 questionnaire. A randomly selected subset of patients (n=29) completed the SWAL-QOL twice to assess test-retest stability. For the patient sample, data on tumor site (oral or oropharyngeal) and stage (I-IV), treatment modality (surgery, radiation, surgery+radiation, chemoradiation), and presence of a PEG tube were abstracted from medical records. Reliability of the SWAL-QOL was high with high internal consistency and test-retest stability. Feasibility was good, except for patients with tube feeding, of whom 38% did not complete the questionnaire (versus 9% of those with oral feeding). A cut-off score of 14 points (or higher) was defined regarding the total SWAL-QOL score to identify patients with swallowing problems with 94% sensitivity and 84% specificity. A difference score of 12 points or more is proposed to be used in study designs with multiple groups. It can be concluded that the SWAL-QOL is a feasible, reliable, and valid questionnaire to assess patients' swallowing impairment. It can be used in future comparative studies for oral and oropharyngeal cancer and in clinical practice to identify patients in need of further diagnostics and/or swallowing rehabilitation services.

Oral squamous cell carcinomas develop in precancerous fields consisting of genetically altered mucosal epithelial cells. These precancerous fields may appear as clinically visible lesions, in particular, oral leukoplakia, but the large majority remains clinically undetectable. The aim of this study was to assess the potential value of a noninvasive screening approach to detect precancerous fields. As a first step, we developed a suitable assay and investigated 25 leukoplakia patients and 20 noncancer control subjects. Exfoliated cells were removed by a brush from multiple small areas of the oral mucosa, including the leukoplakia. Brushed samples were investigated for allelic imbalance (AI) at chromosomes 3p, 9p, 11q, and 17p using microsatellite markers known to show frequent alterations in oral precancer. AI was absent in all (137) of the samples of the 20 control subjects, yielding a specificity of 100%. AI was detected in exfoliated cell samples of 40% (10 of 25) of the leukoplakia lesions studied. Genetic changes were also found outside the leukoplakia lesions. Most frequent was AI at 9p (9 of 10). The noninvasive assay was validated against the biopsy results of the leukoplakia lesions yielding an estimate of sensitivity of 78% (7 of 9) and a positive predictive value of 100% (7 of 7). Altogether, these results show the feasibility of a noninvasive genetic screening approach for the detection and monitoring of oral precancer. This assay could therefore contribute to the secondary prevention of oral squamous cell carcinoma. The assay also shows promise for the detection of precancerous changes that are not macroscopically visible.

Objective: Speech impairment often occurs in patients after treatment for head and neck cancer. New treatment modalities such as surgical reconstruction or (chemo)radiation techniques aim at sparing anatomical structures that are correlated with speech and swallowing. In randomized trials investigating efficacy of various treatment modalities or speech rehabilitation, objective speech analysis techniques may add to improve speech outcome assessment. The goal of the present study is to investigate the role of objective acoustic-phonetic analyses in a multidimensional speech assessment protocol., Patients and Methods: Speech recordings of 51 patients (6 months after reconstructive surgery and postoperative radiotherapy for oral or oropharyngeal cancer) and of 18 control speakers were subjectively evaluated regarding intelligibility, nasal resonance, articulation, and patient-reported speech outcome (speech subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35 module). Acoustic-phonetic analyses were performed to calculate formant values of the vowels /a, i, u/, vowel space, air pressure release of /k/ and spectral slope of /x/., Results: Intelligibility, articulation, and nasal resonance were best predicted by vowel space and /k/. Within patients, /k/ and /x/ differentiated tumor site and stage. Various objective speech parameters were related to speech problems as reported by patients., Conclusion: Objective acoustic-phonetic analysis of speech of patients is feasible and contributes to further development of a speech assessment protocol., (Copyright 2009 S. Karger AG, Basel.)

The common risk factors for oral and oropharyngeal cancer are tobacco smoking and alcohol consumption, and recently the human papillomavirus (HPV) was shown to be involved in a subgroup. HPV-positive and -negative carcinomas can be distinguished on basis of their genetic profiles. Aim of this study was to investigate patterns of chromosomal aberrations of HPV-negative oral and oropharyngeal squamous cell carcinomas (OOSCC) in order to improve stratification of patients regarding outcome. Thirty-nine OOSCCs were classified on basis of their genetic pattern determined by array comparative genomic hybridization (aCGH). Resulting groups were related to patient and tumor characteristics using the Fisher's exact test and in addition to survival with the Kaplan-Meier and log rank tests. Classification distinguished three groups, one characterized by hardly any chromosomal aberration (N=8) and another by a relatively high level (N=26), and one with a very high level (N=5) of chromosomal aberrations. This classification was significantly (p=0.003) associated with survival, with the best survival in the genetically 'silent' group and the worst survival in the most aberrant group. The silent profile was significantly (p<0.05) associated with wild-type TP53, an absence of alcohol consumption and a female gender. These carcinomas were negative for microsatellite instability. This classification of OOSCC was confirmed in an independent set of 89 oral carcinomas. In conclusion, the discovery of these new classes of oral and oropharyngeal cancer with unique genetic and clinical characteristics has important consequences for future basic and clinical studies.

Background: Oral squamous cell carcinomas often develop in a pre-cancerous field, defined as mucosal epithelium with cancer-related genetic alterations, and which may appear as a clinically visible lesion. The test characteristics of three genetic assays that were developed to detect pre-cancerous fields were investigated and compared to histology., Methods: In total, 10 pre-cancerous fields that were not visible at clinical inspection and gave rise to malignant transformation based on an identical TP53 mutation in tumor and mucosal epithelium in the surgical margin, as well as 10 normal oral mucosa specimens were analyzed for numerical chromosomal changes with multiplex ligation-dependent probe amplification (MLPA), for loss of heterozygosity (LOH), with microsatellite PCR and for DNA index alterations with DNA image analysis., Results: No alterations were detected in normal tissue by either of the assays. Both MLPA and LOH assays detected all pre-cancerous fields. DNA cytometry identified aneuploidy in four of 10 pre-cancerous fields, while the corresponding tumors that developed in these fields were shown to be aneuploid., Conclusions: Both the MLPA and LOH assay seem suitable for screening pre-cancerous fields in subjects at high risk for oral cancer even in the absence of clinically abnormal appearing oral mucosa. Measurements of DNA index might be valuable to determine the time to progression.

Background: A Speech Handicap Index (SHI) questionnaire with 30 items on speech problems was developed and validated in 92 patients with cancer of the oral cavity or pharynx and 110 healthy subjects., Methods: All subjects completed the SHI and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Head & Neck module (QLQ-H&N35). Twenty-nine patients completed the SHI twice to assess test-retest reliability., Results: Factor analysis identified 2 well-defined subscales, assessing speech function and psychosocial functioning related to speech. Internal consistency and test-retest reliability were high. Construct validity was evidenced by its ability to distinguish between patient subgroups formed on the basis of tumor grade. A cut-off score of 6 points was defined to identify patients with speech problems., Conclusions: Results of this initial psychometric study indicate that the SHI is a reliable and valid questionnaire for assessing speech problems. Additional research is needed to evaluate responsiveness of the questionnaire to changes in speech-related problems over time.

Several techniques have been developed to reconstruct oral and pharyngeal defects following surgery, in order to restore function and cosmesis. These are primary closure, skin grafts, local transposition of skin, mucosa and/or muscle, regional flaps and free vascularized flaps. Because of the 'bulky', pedicled nature and problems with the donor area of locoregional flaps, and consequently frequently unsatisfactory functional results, free vascularized flaps have gained popularity during the last decade. The authors review the current options available to give physicians, who are not experienced in the field of reconstruction in the head and neck, an impression of the range of techniques available for reconstruction of oral and pharyngeal defects following tumor resection. For reconstruction of oral cavity and pharyngeal defects, fasciocutaneous (e.g. radial forearm and anterolateral thigh flaps) and myocutaneous free flaps (e.g. rectus abdominis and latissimus dorsi) have proven to be very reliable. Free vascularized osteocutaneous flaps (e.g. fibula and iliac crest) permit reconstructive options for bony defects of the mandible or maxilla that can be adapted to a variety of defects. Depending on the site, size and involved tissues of the surgical defect and patient factors, a variety of reconstructive options are available. For both soft tissue and bony defects of the upper aerodigestive tract, microvascular free flaps provide good functional outcomes.

Purpose: The purpose of this study was to evaluate the clinical, pathological, and therapeutic experience of a group of patients with primary oral malignant melanoma (OMM) in Amsterdam, The Netherlands., Patients and Methods: Fourteen patients (5 males, 9 females, mean age 57.9 years) with histopathologic diagnosis of OMM were treated at the Department of Oral and Maxillofacial Surgery/Oral Pathology of the Vrije University Medical Center in Amsterdam between 1978 and 2005. A pigmented, flat or swollen, irregularly bordered lesion of oral mucosa was detected in most patients during the first clinical examination. Pain was the most commonly referred symptom; the palate was the most frequently affected subsite. Following the mucosal melanoma microstaging system, all patients staged as stage I (T any N0M0) could be subclassified as microstage II (invasion up to the lamina propria), except for 1 patient microstaged as stage III (deep skeletal tissue invasion into skeletal muscle, bone, or cartilage). Where possible, surgery was the treatment of choice. Postoperative radiotherapy, using fractions of 6 Gy twice a week for a total dose of 30 Gy, was given to 3 patients. Three patients were treated primarily with radiotherapy alone., Results: Five patients developed local recurrence within 4 to 72 months, and 10 patients developed distant metastases within 6 to 78 months. Ten patients died of their disease within an average interval of 40 months, with a range of 12 to 80 months. Of the 10 patients who qualified for evaluation of the 5-year-survival rate, 1 was alive with disease and 2 were alive without evidence of disease, resulting in a 5-year survival rate of 30%. However, all patients died of their disease before the end of the 10-year follow-up period., Conclusion: Our study confirms that OMM is a rare and aggressive malignancy with a low 5-year survival rate. An evidence-based protocol for the best therapeutic approach is not yet available.

The aim of this study was to document changes from baseline to 6 and 12 months after treatment in health-related quality of life (HRQOL) in relation to sociodemographic and clinical parameters among advanced oral/oropharyngeal cancer patients treated with reconstructive surgery and adjuvant radiotherapy. The HRQOL of 80 consecutive patients was assessed by the EORTC QLQ-C30 and QLQ-H&N35 questionnaires, pretreatment and 6 and 12 months posttreatment. Several patterns of HRQOL changes were distinguished: most general HRQOL issues do not change after treatment or improve compared to baseline scores (emotional functioning, pain, insomnia, constipation) and most head and neck specific issues deteriorate after treatment but return to pretreatment levels at 12 months, except for senses, opening mouth, sticky saliva, and coughing which remain deteriorated in the long term. Although improvement to baseline levels was noted, it should be kept in mind that baseline levels of patients are often deviant from "normal" scores from the general population. Tumour site and stage, comorbidity, and extensive resections were significantly associated with HRQOL outcomes, as were marital status and age. These results, obtained in a homogenous group of patients, may serve as HRQOL benchmarks for future studies investigating surgical and other treatment modalities.

Background: The aim of this study was to analyze swallowing outcome in advanced oral/oropharyngeal cancer patients treated with microvascular reconstructive surgery and adjuvant radiotherapy., Methods: Eighty patients were included. Patient, tumor, and treatment factors were assessed. Postoperative videofluoroscopic swallowing studies (VFSS) and scintigraphy tests were performed at 6 (n = 54 vs 44) and 12 (n = 32 vs 37) months. Swallowing parameters such as the oropharyngeal swallow efficiency and the Penetration/Aspiration Scale were analyzed., Results: Impaired swallowing status was found at 6 months, which remained stationary at 12 months. Comorbid condition, larger tumors (T3-T4 vs T2), and resections of the base of tongue and soft palate combined (vs defects of other dynamic structures) were associated with most profound swallowing problems (p < .05)., Conclusions: Swallowing difficulties are relatively frequent and can to a large extent be predicted. With the knowledge of this study, better counseling and vigilance as to swallowing difficulties may be possible.

We assessed the pretreatment health-related quality of life (HRQOL) and functional status of patients with advanced oral and oropharyngeal cancer. Eighty patients were investigated. HRQOL was assessed by EORTC QLQ-C30/QLQ-H&N35 questionnaires. Functional status assessment comprised speech and oral function tests. The results revealed a wide range of HRQOL and functional deficits before treatment. HRQOL appeared to be related to some extent to tumor site (patients with oral tumors reported more pain compared to patients with oropharyngeal tumors) and tumor classification (patients with T3-T4 tumors reported more trouble opening the mouth and felt more ill compared to patients with T2 tumors). Comorbidity appeared to have a major impact. Patients with comorbidity had significantly worse scores on several scales/items on both the EORTC questionnaires. Functional deficits were related to tumor site, classification and comorbidity. Patients with oral cavity tumors (versus oropharyngeal tumors), patients with T3-T4 tumors (versus T2 tumors), and patients with comorbidity (versus without comorbidity) scored significantly worse on several speech and oral function tests. Impaired speech and oral function appeared to be clearly related to global quality of life (QLQ-C30) and self-reported speech (QLQ-H&N35). Many patients with advanced oral and oropharyngeal cancer have compromised HRQOL and functional status before the start of treatment. In addition to tumor site and tumor classification, comorbidity appears to have a major impact on HRQOL and functional status. Knowledge of pretreatment HRQOL and functional status levels is useful for better understanding the impact of treatment on these outcomes over time.

Background: The use of microvascular free flaps is currently the favored method for the reconstruction of defects after resection of head and neck cancer. The flap most commonly used for head and neck reconstruction is the free radial forearm flap, but the less popular infrahyoid flap represents a good alternative in selected cases. This flap has proven to be helpful in the reconstruction of a wide range of moderate-sized head and neck defects., Methods: We reviewed a series of 13 patients with defects resulting from cancer of the head and neck, who underwent infrahyoid flap reconstruction as an alternative to free radial forearm flap. The series includes 12 squamous cell carcinomas arising from the oral cavity and oropharynx, and 1 Merkel cell carcinoma of the submental skin. In the harvesting of the flap, the technical modifications recently suggested by Dolivet et al were used in all cases. Furthermore, another technical change has been introduced so creating a new infrahyoid facio-myocutaneous flap (IHFMCF). The surgical technique is described in detail., Results: No total or partial flap necrosis was experienced. All reconstructions healed quickly without wound complications and with good functional results. The healing process in the donor site was excellent in every case with good aesthetic results., Conclusions: The IHFMCF is a versatile, reliable, and convenient flap suitable for repairing small and medium-sized defects of the oral cavity and oropharynx and obviates the need for a microvascular reconstruction.

Primary oral malignant melanoma (OMM) is a rare neoplasm, accounting for 0.5% of all oral malignancies. The etiology is unknown; tobacco use and chronic irritation may play some role. Clinically, OMM may mimick other pigmented lesions. A biopsy is required in order to establish the diagnosis. The reported risk of malignant cells spreading during invasive procedures and factors such as size of the lesion or anatomical limitations, may influence the diagnostic surgical procedure. Therapy of OMM is commonly based on surgical excision of the primary tumour, supplemented by radiotherapy, with chemotherapy and immunotherapy serving as adjuncts. Prognosis is poor, with a 5-year survival rate of approximately 15%.

Purpose: The aim of this study was to investigate the prognostic significance of epidermal growth factor (EGFr) expression in oral cavity squamous cell carcinoma (OCSCC) treated with curative surgery and postoperative radiotherapy., Methods and Materials: This retrospective study included 165 OCSCC patients. The expression of EGFr was assessed on paraffin-embedded tissue of the primary tumor by immunohistochemistry using a monoclonal antibody directed against EGFr. Intensity of the EGFr expression was scored by two authors blinded for the clinical outcome., Results: In the univariate analysis, locoregional control at 3 years (LRC) in the EGFr-negative cases was 69% compared with 77% in the EGFr-positive cases (p = 0.22). In the multivariate analysis for local control, a significant interaction was found between EGFr and overall treatment time of radiation (OTT). After stratification for EGFr expression, the OTT was of no importance in the EGFr-negative cases, whereas a significant difference in LRC was found in the EGFr-positive cases, in which the LRC after 3 years was 69% and 94% in case of an OTT of 0-42 days and >42 days, respectively (p = 0.009; hazard ratio = 3.42; 95% confidence interval, 1.28-8.96). No significant association was found between EGFr expression and overall survival., Conclusions: In the present study, no association was found between EGFr expression and outcome regarding locoregional control and overall survival. However, the results of the present study suggest that patients with squamous cell carcinoma of the oral cavity with high EGFr expression benefit more from a reduction of the overall treatment time of postoperative radiation than those with low EGFr expression.

Early diagnosis of oral squamous cell carcinoma (OSCC) may have a major impact on survival and quality of life. Recent studies have shown that the majority of OSCC is preceded by precursor lesions characterized by genetic alterations. The aim of this study was to develop and evaluate a noninvasive screening test for oral preneoplastic lesions, based on genetic alterations as marker. Various methods to obtain a high yield of cells by brushing a small area of the oral mucosa were compared. A novel genetic assay, multiplex ligation-dependent probe amplification (MLPA), was applied that enables the measurement of gains and losses at 40 different chromosomal locations in one PCR reaction using 150 ng DNA. MLPA was performed on DNA of normal and dysplastic oral mucosa as well as of OSCC with the intention to select a specific probe set for accurate detection of precursor lesions in the oral cavity. The assay was correlated to loss of heterozygosity analysis using microsatellite markers, and evaluated on noncancer subjects and patients with oral leukoplakia. A noninvasive sampling method was developed with DNA yields ranging from 150 to 600 ng. Using 120 probes, we could detect large differences with MLPA in the number of alterations between normal vs dysplastic and dysplastic vs tumor tissue with P-values <0.001. A significant correlation was found between the number of alterations as detected by MLPA and the analysis for allelic loss. The available data enabled the selection of a set of 42 MLPA probes, which had the power to optimally discriminate between normal and dysplastic tissue. Our data show that MLPA is a sensitive, reliable, high-throughput and easy-to-perform technique, enabling the detection of genetic alterations on small noninvasive samples and can be considered a promising method for population-based screening of preneoplastic lesions in the oral cavity.

Background: The aim of the study was to analyze speech outcome for patients with advanced oral/oropharyngeal cancer treated with reconstructive surgery and adjuvant radiotherapy., Methods: Speech tests (communicative suitability, intelligibility, articulation, nasality, and consonant errors) were performed in a control group and in patients before treatment (n = 76), and 6 months (n = 51) and 12 months (n = 42) after treatment., Results: Speech tests were significantly worse for patients before and after treatment compared with the controls. Speech did not improve between 6 and 12 months. After treatment, patients with T3-4 tumors showed a significantly worse score for communicative suitability, intelligibility, and articulation than patients with T2 tumors. No significant differences were found for subsites after treatment, although patients with mobile tongue tumors showed the best results., Conclusion: Speech difficulties are significant, and with the knowledge of this study better counseling and vigilance as to speech difficulties may be possible in patients undergoing treatment for oral/oropharyngeal cancer., ((c) 2005 Wiley Periodicals, Inc.)

The aim of the study was to investigate the possible impact of comorbidity on survival of patients undergoing composite resection and microvascular reconstruction for oral/oropharyngeal cancer. Patient, tumour and treatment data were recorded. Comorbidity was graded by the Adult Comorbidity Evaluation (ACE-27) test. Survival and statistics were calculated. Comorbidity score ACE-27 grade 2 was present in 47% of patients, for ACE-27 grade 3 this was 13%. The median follow-up was 50 (3-87) months. Thirty-eight patients died, 32 developed a recurrence. Comorbidity score ACE-27 grade 3 turned out to be a clear predictor for overall survival (p<0.05). For ACE-27 grade 3 (n=13) 5-years survival was 29%, for ACE-27 grade 2 (n=87) this was 64%. No multivariate influences on the effects of comorbidity were found. Improved knowledge of the effect of comorbidity on survival may lead to better patient selection and counselling for major surgery and microvascular reconstruction.

Background: In patients with head and neck squamous cell carcinoma (HNSCC), the presence of lymph node metastases is the most important prognosticator. Sentinel node (SN) biopsy has been shown to be an accurate staging technique for patients with breast cancer and melanoma and might also be suited for patients with HNSCC. This study was undertaken to determine whether the SN concept holds true for HNSCC and could be exploited for SN biopsy., Methods: In 22 patients with T2 to T4 N0 oral or oropharyngeal squamous cell carcinoma (SCC) who were scheduled to undergo combined primary tumor excision and elective unilateral (n = 17) or bilateral (n = 5) neck dissection, SN identification was performed the day before surgery by use of lymphoscintigraphy after peritumoral injections of 99mTc-labeled colloidal albumin. After the neck dissection specimens were removed, all SNs, all other radioactive lymph nodes, and all nonradioactive lymph nodes were retrieved for histopathologic analysis, including serial sectioning at 250-microm intervals and immunohistochemical analysis (IHC)., Results: Overall, in 21 (78%) of 27 neck sides, an SN was identified by scintigraphy. Of the six neck sides in which SNs were not identified by scintigraphy, four were from three patients who underwent bilateral neck dissection. In another patient treated by bilateral neck dissection, the SN identified by scintigraphy could not be found in the specimen. In the remaining 20 neck dissection specimens, 23 SNs and 30 additional radioactive lymph nodes could be found. At histologic examination of the 20 neck specimens in which the SN was found, at least one SN was tumor positive in eight cases. In one neck specimen, a metastasis was detected in a nonradioactive lymph node, whereas the SN was tumor free, also at serial sectioning and IHC. In the remaining 11 neck sides in which the SN was tumor negative, none of the other radioactive (n = 13) and none of the nonradioactive (n = 279) lymph nodes contained tumor at histopathologic analysis, including serial sectioning and IHC. The sensitivity of the SN procedure for predicting lymph node metastases, therefore, was 89% (eight of nine neck specimens) when an SN was identified by scintigraphy and found in the specimen. The overall accuracy of the SN procedure for predicting the presence or absence of lymph node metastases in the neck was 95% (19 of 20 neck specimens)., Conclusions: Our study seems to validate the SN hypothesis for oral and oropharyngeal cancer. The role of SN biopsy in the management of the N0 neck in such patients has yet to be established through prospective trials. SN identification (and thus biopsy) does not seem to be reliable in patients with tumors located in or close to the midline., (2004 Wiley Periodicals, Inc.)

The capability of modern imaging techniques such as CT, MRI, US and US-guided fine-needle aspiration cytology (USgFNAC) to detect small tumour deposits is limited. Therefore, the detection of occult metastases in the clinically negative neck remains a diagnostic problem. One of the novel options to refine staging of head and neck cancer is [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET). To evaluate the diagnostic value of FDG-PET in the detection of occult malignant lymph nodes, we compared the results of FDG-PET with other diagnostic techniques and the histopathological outcome of 15 neck dissection specimens from 15 head and neck cancer patients with a clinically negative neck. Three sides contained metastases of squamous cell carcinoma. FDG-PET enabled detection of metastases in two sides, which were also detected by MRI or USgFNAC. FDG-PET and CT missed metastases in one patient, which were detected by both MRI and USgFNAC. In studies with a detailed examination of lymph nodes of a neck dissection, a low sensitivity of FDG-PET for the detection of occult lymph node metastases is found. It is unlikely that FDG-PET is superior in the detection of occult lymph node metastases in head and neck cancer patients with a palpably negative neck. The histopathological method used seems to be the most important factor for the differences in sensitivity in reported FDG-PET studies. New approaches such as the use of monoclonal antibodies labelled with a positron emitter may improve the results of PET in these patients.

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.

Background: Identification of factors, especially comorbidity, that affect the incidence and severity of complications in head and neck cancer patients., Methods: One hundred patients with an oral/oropharynx carcinoma undergoing composite resection and microvascular soft tissue transfer were analyzed. Patient data and tumor and treatment factors were recorded. Comorbidity was graded by an Adult Comorbidity Evaluation 27 (ACE-27) test. Postoperative complications were scored according to their severity., Results: Comorbidity score ACE-27 grade 2 or higher was present in 47% of patients, whereas 33% had a clinically important complication develop. A comorbidity score of ACE-27 grade > or =2 was a strong predictor for complications (p <.001). There were no other predictors for postoperative complications., Conclusions: Comorbidity is of great importance for prediction of postoperative complications in head and neck cancer patients, especially an ACE-27 grade > or =2. It may be concluded from these results that prevention of complications should focus on comorbidities., (Copyright 2003 Wiley Periodicals, Inc.)

Histological grading of epithelial dysplasia in the oral cavity and oropharynx is used to predict the risk for cancer and to determine the treatment strategy. This grading, however, is subjective and not well reproducible. Recent publications have shown that molecular markers are promising in cancer risk assessment. The aim of the present study was to compare classical histological and molecular grading and to relate these to the proliferation rate by quantitative assessment of Ki-67 staining. Forty-three samples were analysed from the margins of patients who had undergone resection of their squamous cell carcinoma in the oral cavity/oropharynx. Three experienced pathologists performed the histological grading. With the consensus score, 12 samples were classified as normal and 31 as dysplastic (21 mild, six moderate, and four severe). Loss of heterozygosity (LOH) was assessed in the same samples with 15 microsatellite markers at chromosomes 3p, 9p, 17p, 8p, 13q, and 18q, and was present in 28 of the 43 samples. Twenty-four of the 28 cases (86%) with LOH were classified as dysplastic and four as normal. All ten samples with moderate and severe dysplasia and 14 of 21 samples with mild dysplasia contained LOH. In four of 12 biopsies classified as normal, LOH was found. A very striking and significant difference of the Ki-67 index was observed between LOH-positive and LOH-negative cases, 36.6 +/- 11.1% versus 19.4 +/- 2.8% positive cells, respectively. In mild dysplasia, 13 of 14 lesions containing LOH had a higher Ki-67 index than all seven lesions without LOH. Thus, in the oral cavity/oropharynx, LOH is more frequently found in the histologically higher-grade lesions (moderate dysplasia or worse) and in the lower grade lesions when a high proliferation rate is present. Assessment of proliferation with Ki-67 is a better surrogate for LOH than histological grading., (Copyright 2003 John Wiley & Sons, Ltd.)

The development of second primary tumors has a negative impact on the prognosis of head and neck squamous cell carcinoma. Previously, we detected genetically altered and tumor-related mucosal lesions in the resection margins in 25% of unselected head and neck squamous cell carcinoma patients (Tabor MP, Brakenhoff RH, van Houten VMM, Kummer JA, Snel MHJ, Snijders PJF, Snow GB, Leemans CR, Braakhuis BJM: Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 2001, 7: 1523-1532). The aim of this study was to determine whether first and second primary tumors are clonally related and originate from a single genetically altered field. From 10 patients we analyzed the first tumor of the oral cavity or oropharynx, the >3-cm remote second primary tumor, and the mucosa from the tumor-free margins from both resection specimens. We compared TP53 mutations and loss of heterozygosity profiles using 19 microsatellite markers at chromosomes 3p, 9p, 13q, and 17p. In all patients, genetically altered mucosal lesions were detected in at least one resection margin from both first and second primary tumor. Evidence for a common clonal origin of the first tumor, second primary tumor, and the intervening mucosa was found for at least 6 of 10 patients. Our results indicate that a proportion of multiple primary tumors have developed within a single preneoplastic field. Based on different etiology and clinical consequences, we propose that independent second primary tumors should be distinguished from second field tumors, that arise from the same genetically altered field the first tumor has developed from.