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BackgroundBase of tongue cancer incidence and patient survival is increasing why treatment sequelae becomes exceedingly important. Osteoradionecrosis (ORN) is a late adverse effect of radiotherapy and brachytherapy (BT) could be a risk factor. Brachytherapy is used in three out of six health care regions in Sweden.AimsInvestigate if patients treated in regions using BT show an increased risk for ORN and whether brachytherapy has any impact on overall survival.Material and MethodsWe used data from the Swedish Head and Neck Cancer Register between 2008-2014. Due to the nonrandomized nature of the study and possible selection bias we compared the risk for ORN in brachy vs non-brachy regions.ResultsFifty out of 505 patients (9.9%) developed ORN; eight of these were treated in nonbrachy regions (16%), while 42 (84%) were treated in brachy regions. Neither age, sex, TNM-classification/stage, p16, smoking, neck dissection, or chemotherapy differed between ORN and no-ORN patients. The risk for ORN was significantly higher for patients treated in brachy regions compared to non-brachy regions (HR = 2,63, p = .012), whereas overall survival did not differ (HR = 0.95, p = .782).Conclusions and SignificanceBrachytherapy ought to be used cautiously for selected patients or within prospective randomized studies.

To better identify patients with human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) and a poor prognosis after treatment, we compared the gene expression in tumours from patients with a poor or a favourable prognosis in a case-control setting. The results were thereafter validated in two separate cohorts on the RNA and protein levels. High RNA or protein expression of FGF11 was correlated with a poor patient survival in all three cohorts. Taken together, the data imply that FGF11 may play a major role in the prognosis of patients and that FGF11 could serve as a prognostic marker in HPV-positive oropharyngeal cancer.Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis. It has therefore been suggested that treatment should be individualized and separated by HPV status. However, additional prognostic markers are still needed before treatment can be individualized for this patient group. For this purpose, all patients diagnosed with HPV and p16-positive OPSCC in Stockholm 2000-2009, identified as having a partial/nonresponse to treatment and having viable tumour cells in their neck specimen with material available were categorized as cases. These were matched to controls (complete responders), and the differences in the gene expression were analysed. Two separate verification cohorts were identified including patients with HPV- and p16-positive OPSCC, and the data from the case-control study were verified by qPCR and immunohistochemistry (IHC) in the respective cohorts. A separation of gene expression in correlation with survival was observed in the case-control study, and FGF11 expression was identified as significantly differently expressed between the two groups. The prognostic role of FGF11 was validated in the two cohorts on the RNA and protein levels, respectively. Taken together, our findings suggest that FGF11 may indicate a poor prognosis in HPV-positive OPSCC and may serve as a prognostic biomarker.

Ranula is a rare benign cystic lesion in the floor of the mouth, which can herniate through the mylohyoid muscle and become a plunging ranula. Treatment for ranulas is currently surgical excision of the sublingual gland. Sclerotherapy with OK-432 is a well-established treatment of lymphatic malformations, but not yet thoroughly evaluated on ranulas. Objectives: To evaluate sclerotherapy of ranulas with OK-432 in a randomized double-blinded trial.20 patients with plunging or intraoral ranula were randomized to two double-blinded injections with OK-432 or saline. Effect on the ranula and evaluation of symptoms and QOL were investigated.Treatment response differed significantly between OK-432 and placebo,This study suggests that sclerotherapy with OK-432 in ranula is a very effective treatment for intraoral ranulas, but possibly less useful in plunging ranulas.This is a limited study, but we believe that sclerotherapy with OK-432 should be recommended as primary treatment at least for intraoral ranulas.

Anticancer immunotherapies have revolutionized cancer management, yet the effect of systemic anti‐programmed cell death protein 1 (PD‐1) treatment is predominantly studied in tumor‐infiltrating lymphocytes (TILs). Its impact on PD‐1 expressing cells in tumor‐draining lymph nodes (TDLNs) is not well understood and yet to be explored. Thus, further research aiming for better understanding of the PD‐1 pathway not only in tumor tissue but also in TDLNs is warranted. In this study, we investigated the expression of PD‐1, CD69, and HLA‐DR on CD4+ and CD8+ T cells by flow cytometry analysis of peripheral blood mononuclear cells (PBMCs), TDLNs, and tumor samples from patients with oral squamous cell carcinoma (OSCC). Our data showed that both helper and cytotoxic T lymphocytes in OSCC tissue were highly activated and expressed high level of PD‐1 (over 70% positivity). Lymphocytes in TDLNs and peripheral blood expressed significantly lower levels of PD‐1 and other activation markers compared to TILs. Moreover, we demonstrated that a significant fraction of PD‐1 negative TILs expressed high levels of human leukocyte antigen – DR isotype and CD69. In contrast, PD‐1 negative cells in TDLNs and PBMCs scarcely expressed the aforementioned activation markers. Furthermore, we proved that patients with a high percentage of CD3+ PD‐1+ cells in tumor‐draining lymph nodes had significantly lower disease‐free and overall survival rates (log‐rank test P = .0272 and P = .0276, respectively). Taken together, we proved that flow cytometry of lymph nodes in OSCC is feasible and may be used to investigate whether PD‐1 levels in TDLNs correspond with survival and potentially with response to anti‐PD‐1 therapy. Such knowledge may ultimately help guide anti‐PD‐1 treatment., Flow cytometry is a powerful tool that can be used in head and neck cancers to investigate immunological milieu of tumor‐draining lymph nodes. In this project, we provide a characterization of T cells within head and neck cancer tumors, tumor‐draining lymph nodes, and blood.

Simple Summary Long-term survival in patients with oropharyngeal cancer is sparsely studied, but atypical recurrences in human papillomavirus-positive (HPV+) oropharyngeal cancer have been indicated. Furthermore, while the role of HPV is well established in tonsillar and base of tongue cancer, the dominant oropharyngeal subsites, its role in the minor oropharyngeal sites (the oropharyngeal walls, the uvula, and the soft palate) is not fully elucidated. The aim of this retrospective study was therefore to assess long-term outcome in relation to oropharyngeal sub-sites and HPV/p16 status. We confirm the prognostic role of p16+ in tonsillar and base of tongue cancer, but not the other sites. We find that combined HPV/p16-status gives better prognostic information than p16 alone. Lastly, we show that p16− cancer has more locoregional and late recurrences compared to p16+ cancer. Consequently, only combined HPV/p16 positivity in patients with tonsillar and tongue base cancer should be used in future treatment de-escalation trials. Abstract Long-term survival data in relation to sub-sites, human papillomavirus (HPV), and p16INK4a (p16) for patients with oropharyngeal squamous cell carcinoma (OPSCC) is still sparse. Furthermore, reports have indicated atypical and late recurrences for patients with HPV and p16 positive OPSCC. Therefore, we assessed long-term survival and recurrence in relation to oropharyngeal subsite and HPV/p16 status. A total of 529 patients with OPSCC, diagnosed in the period 2000–2010, with known HPVDNA and p16-status, were included. HPV/p16 status and sub-sites were correlated to disease-free and overall survival (DFS and OS respectively). The overexpression of p16 (p16+) is associated with significantly better long-term OS and DFS in tonsillar and base of tongue carcinomas (TSCC/BOTSCC), but not in patients with other OPSCC. Patients with HPVDNA+/p16+ TSCC/BOTSCC presented better OS and DFS compared to those with HPVDNA−/p16− tumors, while those with HPVDNA−/p16+ cancer had an intermediate survival. Late recurrences were rare, and significantly more frequent in patients with p16− tumors, while the prognosis after relapse was poor independent of HPVDNA+/−/p16+/− status. In conclusion, patients with p16+ OPSCC do not have more late recurrences than p16−, and a clear prognostic value of p16+ was only observed in TSCC/BOTSCC. Finally, the combination of HPVDNA and p16 provided superior prognostic information compared to p16 alone in TSCC/BOTSCC.

Distinguishing branchial cleft cysts (BCCs) from cystic metastases of a human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Fine needle aspirates (FNAs) from cystic metastasis may be non-representative, while reactive squamous cells from BCC can be atypic. Based on cytology and with the support of HPV DNA positivity many centers treat cystic metastasis oncological and thus patients are spared neck dissection. To do so safely, one must investigate whether HPV DNA and p16DNA was extracted from formalin fixed paraffin embedded (FFPE) surgically resected BCCs from 112 patients diagnosed 2007-2015 at Karolinska University Hospital and amplified by PCR. A multiplex bead-based assay used to detect 27 HPV-types and p16All 112 BCCs were HPV DNA negative, and of 105 BCCs possible to evaluate for p16HPV DNA and p16

Background: Rising incidence of oropharyngeal cancers in numerous countries since the 1970s has been attributed to increased oral human papillomavirus (HPV) exposure. However, the contribution of coincidental declines in the surgical removal of the tonsils (tonsillectomy) is unknown. We quantified the association of tonsillectomy with risk of tonsillar, other oropharyngeal, and other head and neck cancers and the contribution of declines in tonsillectomies to cancer incidence trends. Methods: We conducted a nation-wide cohort study in Sweden (1970–2009). Tonsillectomies (N = 225,718) were identified through national patient registers, which were linked with the cancer register. Cancer incidence in the tonsillectomy cohort was compared with Sweden's general population through standardized incidence ratios (SIR). Results: Tonsillectomies were associated with reduced risk of tonsil cancers [SIRs 1+ years post-tonsillectomy = 0.31; 95% confidence interval (CI), 0.08–0.79 and 5+ years post-tonsillectomy = 0.17; 95% CI, 0.02–0.62], but unrelated to other oropharyngeal or other head and neck cancers (SIRs 1+ years post-tonsillectomy = 1.61; 95% CI, 0.77–2.95 and 0.92; 95% CI, 0.64–1.27, respectively). The cumulative incidence of tonsillectomy declined significantly (40%–50%) during 1970–2009. However, tonsil cancer incidence significantly increased during 1970–2009 both without and with corrections for declines in tonsillectomies (relative risks per 5-year periods = 1.23, P < 0.001 and 1.20, P < 0.001, respectively). Conclusions: The reduced tonsil cancer risk with tonsillectomy reflects the removal of most of the relevant tissue. The absence of associations with other head and neck cancers indicates that tonsillectomy may not impact carcinogenesis at other sites. Impact: The significant increases in oropharyngeal cancer incidence since the 1970s in Sweden appear independent of declines in tonsillectomies, reinforcing increased oral HPV exposure as the likely cause. Cancer Epidemiol Biomarkers Prev; 25(6); 944–50. ©2016 AACR.

summary Material and methods: Presence of HPV DNA was analyzed in mouthwash and tonsillar swab samples, if indicative of HPV-positive tonsillar or base of tongue cancer in 76 patients, with suspected head neck cancer, undergoing diagnostic endoscopy at Karolinska University Hospital. The diagnosis and tumor HPV status was later obtained from patients’ records. As controls, 37 tumor-free dental visitors were included. Results: Of the 76 patients, 22/29 (76%) and 16/18 (89%) had an HPV-positive tonsillar and base of tongue cancer respectively, with 18/22 (82%) and 8/16 (50%) respectively having tumor concordant HPV-type positive oral samples. Two other HPV-positive oral samples in the base of tongue cancer group did not correlate to the tumor HPV status. Among the remaining patients, 19 with other head neck cancer and 10 with benign conditions, 4/29 (14%) had HPV-positive oral samples. Consequently, of the HPV-positive oral samples, dominated by HPV16 and high signals, 27/32 (84%) were derived from 26 patients with concordant HPV-type positive tonsillar or base of tongue cancer and one patient with an unknown primary head and neck cancer. The other five HPV-positive oral samples, with mainly low signals were derived from two patients with non-concordant HPV-type positive tumor biopsies, two patients with HPV-negative tumor biopsies and a patient with a benign condition. Of the dental patients, 3/37 (8%) had HPV-positive tonsillar swabs with weak signals. Conclusion: In patients with suspected head neck cancer, HPV-positive oral samples, especially HPV16 with high signals, could be indicative of HPV-positive tonsillar or base of tongue cancer.

Patients with cancer of unknown primary (CUP) in the head neck region are generally treated with neck dissection followed by radiotherapy at times combined with chemotherapy, a treatment associated with considerable side effects. Some of these tumors may originate as human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OSCC), with better clinical outcome than head neck squamous cell cancer (HNSCC) in general, and could potentially do well with less treatment. Here, we therefore investigated whether HPV status and p53-expression correlated to clinical outcome in patients with CUP in the head neck region. Fifty metastases were analyzed for presence of HPV DNA, and expression of p16INK4A and p53 and the data were correlated to clinical outcome. Patients with HPV DNA-positive (HPVDNA+) metastases had significantly better 5-year overall survival (OS) compared to those with HPVDNA− metastases (80.0% vs. 36.7%, respectively; P = 0.004), with a similar tendency for disease-free survival (DFS). These survival rates showed excellent concordance with those of HPVDNA+ and HPVDNA− OSCC in Sweden during the same time period, strengthening the hypothesis that HPVDNA+ head and neck CUP may originate from HPVDNA+ OSCC. In addition, having absent/intermediary-low as compared to high expression of p53 correlated to a better prognosis with a 69% as compared to 14% 5-year OS, respectively (P

Tonsillar, base of tongue and tongue cancer have similar anatomical and histopathological appearances but present differences in prognosis. Human papillomavirus (HPV) is a known risk factor for tonsillar and base of tongue cancer, and a survival benefit has been shown for these tumors; however, HPV prevalence in tongue cancer is low. Tonsillar, base of tongue and tongue cancer patients registered in the Swedish Cancer Registry between 1960 and 2004 were followed from the date of cancer diagnosis until death, emigration out of Sweden, or the end of a follow-up (5 years since cancer diagnosis), whichever occurred first. The relative survival rate was computed as the ratio of the observed to the expected survival rate, in which the latter was inferred from the survival of the entire Swedish population in the same age, sex and calendar year stratum. The relative survival rate has improved significantly over time for patients with tonsillar and base of tongue cancer although delineated by different patterns. However, the relative survival rate in tongue cancer patients exhibited only a very modest improvement during the same time period. Contrary to the overall improved survival for patients with tonsillar and base of tongue cancer, the patients with tongue cancer show a very modest improvement in Sweden since 1960. Further studies are warranted to elucidate more effective treatment options for tongue cancer patients.

J Oral Pathol Med (2010) 40: 385–389 Background: Cyclooxygenase-2 expression is associated with unfavorable outcome in various cancers, and evidence is accumulating that carcinogenesis possibly evolves from intracellular changes in response to induction of this enzyme. Today selective cyclooxygenase-2 inhibitors are being studied and used as complement in cancer treatment. This study examined the prognostic value of cyclooxygenase-2 expression in oral tongue squamous cell carcinoma (OTSCC). Methods: Expression of cyclooxygenase-2 was determined in biopsies from 76 stage matched patients with OTSCC by immunohistochemistry between January 2000 and December 2004 in Stockholm, Sweden. Additionally, twelve samples taken after pre-operative radiotherapy were investigated. Results: All OTSCC specimen expressed cyclooxygenase-2 by immunostaining. The cyclooxygenase-2 staining intensity increased significantly with more advanced stage (P = 0.020). Fifty percent of the surgical specimen showed a decrease in immunostaining post-radiation (P = 0.031). No association was found with survival. Conclusion: Cyclooxygenase-2 expression has limited prognostic value in OTSCC.

New promising therapeutic agents targeting epidermal growth factor receptor (EGFR) have been developed although clinical information concerning EGFR status in oral tongue squamous cell carcinoma (OTSCC) is limited. We investigated EGFR protein expression and gene copy numbers in 78 pretreatment OTSCC paraffin samples. EGFR protein expression was found in all 78 tumours, of which 72% showed an intense staining. Fifty-four percent of the tumours had high (≥four gene copies) EGFR gene copy numbers. EGFR gene copy number was significantly associated with EGFR protein expression (P = 0.002). Pretreatment EGFR staining intensity tended to be associated with non-pathological complete remission after preoperative radiotherapy for Stage II OTSCC. No correlation was found between EGFR status and survival. EGFR FISH results were significantly (P = 0.003) higher in more advanced tumours (Stages II, III and IV) than in the tumours in Stage I. Non-smokers exhibited a significantly higher EGFR gene copy number and protein overexpression in Stages I and II OTSCC than smokers (P = 0.001, P = 0.009). In conclusion, EGFR was found to be overexpressed in all OTSCCs making this cancer type interesting for exploring new therapeutic agents targeting the EGFR receptor.

Aims: To investigate the Voice Handicap Index (VHI), the health-related quality of life (HRQL), and the correlations between VHI and HRQL in laryngectomees. Methods: Forty-three laryngectomized persons participated (mean age 68;6 years, time since laryngectomy between 0;6 and 12 years). Evaluation of voice handicap was done with the VHI. HRQL was evaluated with questionnaires from the European Organization for Research and Treatment of Cancer, EORTC QLQ-C30 and EORTC QLQ-H&N35. Results: VHI for the whole group demonstrated a moderate voice handicap, with a mean score of 48/120. The functional scales of EORTC QLQ-C30 resulted in scores on the same level as the normal population with the exception of a lower global quality of life scale (Global QOL). EORTC QLQ-H&N35 revealed problems with smell and taste, speech, coughing, xerostomia, and sexuality. VHI correlated significantly with the Global QOL, the functional scales, dyspnea, pain, nausea and financial difficulties (EORTC QLQ-C30). Significant correlations were also found between VHI and speech problems, social contact, pain from the head and neck area, sense problems, sexuality and social eating (EORTC QLQ-H&N35). Conclusion: The EORTC questionnaires in combination with the VHI questionnaire seem to capture most of the problems following laryngectomy, including voice problems.

This study aimed to relate the results of physiological measurements of the pharyngoesophageal (PE) segment in subjects using tracheoesophageal (TE) or esophageal (E) speech with perceptual assessment of the speakers' voice quality and acoustic measurements of the voice function. It further aimed to investigate possible differences in appearance and placement of the voice source between TE and E speakers. Nine subjects who had undergone a laryngectomy (five TE speakers and four E speakers) participated in the study. They were videoradiographically examined during phonation and silence. Measurements were made of size and placement of the PE segment, the distance between the PE segment and the anterior wall, and the distance between the posterior and anterior esophageal walls beneath the segment. Five trained listeners perceptually assessed the subjects' voice quality, and acoustical analyses of fundamental frequency and sound pressure level were made. The physiological measurements of the nine subjects' individual PE segments varied in terms of appearance and placement during both phonation and silence, but all of the subjects showed a good closure at the PE segment level during phonation. Statistically significant results were found between all of the physiological measurements of the PE segment. Significant results were also found between the acoustical and perceptual assessments of the subjects' voices. No relations were found between the physiological measurements and the acoustic and perceptual results. The conclusion of this study was that there were no specified differences in the PE segment between TE speakers and E speakers, but that there were large individual differences within each speaker group.

From 1970 to 2002 in the Stockholm area, we revealed a parallel three-fold increase in the incidence of tonsillar cancer and the proportion of human papillomavirus (HPV) positive tonsillar cancer cases, indicating a possible role of HPV infection in this disease. We have now examined whether HPV and viral load in pre-treatment tonsillar cancer biopsies correlates to disease prognosis, and whether the presence of HPV-16 E6 and E7 mRNA could be ascertained. The presence of HPV-16, but not viral load, in tonsillar cancer was shown to be a favourable prognostic factor for clinical outcome. Moreover, E6 and/or E7 were expressed in almost all assessable HPV-16 positive cases, supporting an oncogenic role of HPV-16 in tonsillar cancer.

Smoking and alcohol are well-known etiological factors in tonsillar cancer. However, as in cervical cancer, human papillomavirus (HPV) is currently found in a sizable proportion of tonsillar cancer. Recent reports from the U.S. and Finland show an increase in the incidence of tonsillar cancer, without a parallel rise in smoking and alcohol consumption. This study investigates whether the incidence of tonsillar cancer has also changed in Sweden and whether a possible explanation of the increase is a higher proportion of HPV-positive tonsillar cancer. The incidence of tonsillar cancer between 1970 and 2002 in the Stockholm area was obtained from the Swedish Cancer Registry. In parallel, 203 pretreatment paraffin-embedded tonsillar cancer biopsies taken during 1970-2002 from patients in the Stockholm area were tested for presence of HPV DNA by PCR. The incidence of tonsillar cancer increased 2.8-fold (2.6 in men and 3.5 in women) from 1970 to 2002. During the same period, a significant increase in the proportion of HPV-positive tonsillar cancer cases was observed, as it increased 2.9-fold (p < 0.001). The distribution of HPV-positive cases was 7/30 (23.3%) in the 1970s, 12/42 (29%) in the 1980s, 48/84 (57%) in the 1990s and 32/47 (68%) during 2000-2002. We have demonstrated a highly significant and parallel increase both in the incidence of tonsillar cancer and the proportion of HPV-positive tumors. Hence, HPV may play an important role for the increased incidence of tonsillar cancer. This should definitely influence future preventive strategies as well as treatment for this type of cancer.

The frequency of human papilloma virus (HPV) and its influence on clinical outcome was analyzed retrospectively in pre-treatment paraffin embedded biopsies from 110 patients with tongue cancer. The presence of HPV DNA was examined in 85 mobile tongue tumors and 25 base of tongue tumors by a polymerase chain reaction (PCR) with 2 general primer pairs, GP5+/6+ and CPI/IIG. When HPV-DNA was found, HPV-type specific primers and direct sequencing were used for HPV sub-type verification. Twelve of 110 (10.9%) samples were HPV-positive; 9 for HPV-16, 1 for HPV-33, 1 for HPV-35 and 1 could not be analyzed because of shortage of DNA. HPV was significantly more common in base of tongue tumors (10/25, 40.0%) compared to tumors of the mobile tongue (2/85, 2.3%). The influence of HPV on clinical outcome in mobile tongue cancer could not be studied, due to that HPV was present in too few cases. Of the 19 patients with base of tongue cancer that were included in the survival analysis, however, 7 patients with HPV-positive base of tongue cancer had a significantly favorable 5-year survival rate compared to the 12 HPV-negative patients. In conclusion, HPV is significantly more common in base of tongue cancer than in mobile tongue cancer, and has a positive impact on disease-specific survival in patients with base of tongue cancer.

Our aim was to map and compare genomic imbalances in human papillomavirus (HPV)-positive and -negative squamous cell carcinomas of the tonsil. Twenty-five primary carcinomas were analyzed by comparative genomic hybridization. Fifteen (60%) were found to be HPV-positive by PCR, and the majority were HPV-16. There were statistically significant differences in the distribution of DNA gains and losses between the HPV-positive and -negative samples. Eleven of 15 HPV-positive samples (73%) showed gain on chromosome 3q24-qter, while only 4/10 (40%) HPV-negative samples had the same gain (p = 0.049). Furthermore, 4/10 (40%) HPV-negative samples but no HPV-positive samples had gain on chromosome 7q11.2-q22 (p = 0.017). As expected, and similar to previous studies, patients with an HPV-positive tumor had a statistically significantly better disease-specific survival than patients with an HPV-negative tumor (p = 0.002). The most common changes, e.g., gain on 3q or 8q, loss on 11q or 13 and loss on chromosome 7q in HPV-negative tumors, did not have any influence on prognosis. However the number of cases in each subgroup was limited. © 2003 Wiley-Liss, Inc.

It is not uncommon for head and neck cancer patients to present with neck node metastases. Standard treatment for patients in whom no primary tumor is found include surgery and radiotherapy but there is still controversy about the type and extent of treatment. A retrospective review was carried out on 51 consecutive patients with cervical lymph node metastases of unknown origin, treated between 1980 and 1994 at Radiumhemmet, Karolinska Hospital. All patients received radiotherapy to the ipsilateral neck and the corresponding mucosa and surgery was performed in 55% of cases. The 5-year overall survival rate was 41%. A primary tumor was later found in 6 cases (12%). Two cases of cancer were detected after 5 years and classified as 'second primaries'. Results from this small retrospective material have to be interpreted with caution but indicate that limited, ipsilateral radiotherapy to mucosa and lymph nodes combined with surgery, when possible, may be justified.

AIM: To assess the clinical value of malignancy grading systems compared with nuclear DNA content, protein p53, and angiogenesis for predicting recurrence of stage I (UICC, 1987) tongue carcinomas. METHODS: Histopathological malignancy grading according to Jakobsson and tumour front grading according to Bryne et al were performed on haematoxylin and eosin slides. DNA analysis was performed by image cytometry. Protein p53 and angiogenesis were evaluated by immunohistochemical analysis using antibody CM1 and antibody against factor VIII related antigen, respectively. RESULTS: 49 patients with stage I carcinomas of the mobile tongue were included, all treated by local surgical excision alone. Eight patients (16%) suffered from local recurrence during follow up, and 13 (27%) had regional recurrence. Both Jakobsson's malignancy grading system and p53 immunoreactivity proved to be useful predictors of regional recurrence in a Cox multivariate regression analysis. CONCLUSIONS: Histopathological malignancy grading systems provide valuable prognostic information and can still compete with current biological markers in this respect.

Background: Squamous epithelial cancer can develop from progressive epithelial changes connoted dysplasias. Histopathologic evaluation/grading of these lesions is difficult and gives poor information concerning the risk for progression to cancer. Squamous cell carcinoma of the head and neck (SCCHN) frequently show p53 alteration and DNA-ploidy aberration. Could these markers be used as indicators for malignancy risk in the larynx? Methods: Immunohistochemical staining (IHC), with the CM-1 antibody against p53, and image cytometry (ICM) DNA analysis were performed in 60 lesions from 12 patients-and 21 controls-who were initially seen with laryngeal lesions prior to cancer in situ (cis) or invasive cancer diagnosis at the same site. Results: All but one of the invasive cancers, and 77% of the lesions which preceded cancer or cancer in situ, showed positive p53 immunostaining, as compared with only 10% of the controls. All but one of the invasive cancer lesions, and 77% of the precancerous lesions, showed aberrant DNA-ploidy results, whereas all controls were diploid. When DNA and p53 analysis were combined, only one of the lesions preceeding cis or invasive cancer was negative. Conclusions: Both p53 immunoreactivity and DNA-ploidy aberration appear to be early events in the multistep process of squamous epithelial carcinogenesis. Immunohistochemical staining p53 analysis and ICM DNA analysis does increase the diagnostic sensitivity for cancerous and true precancerous lesions in the larynx.

Background. Clinical evaluation of preneoplastic lesions of the oral cavity is difficult. Histopathologic grading of dysplasias shows large variability and does not give reliable information concerning the risk for progression to cancer. Methods. DNA image cytometry and p53 immunostaining were performed to describe the pattern of DNA aberration and p53 overexpression in confined preneoplastic lesions and in the subsequent carcinomas developing at the same site in 20 patients. Results. Hyperplastic and/or inflammatory lesions showed a diploid DNA pattern in 81% of the cases and 23% were p53-positive. Dysplastic preneoplastic lesions showed a nondiploid/ aneuploid DNA pattern in 73% and 64% were p53-positive. The subsequent invasive carcinomas were nondiploid/aneuploid in 86% and p53-positive in 69% of cases. Conclusions. Analysis of nuclear DNA content and p53 immunostaining appears to be useful as an adjunct to histopathology in the evaluation of true precancerous lesions.

Cyclooxygenase-2 expression is associated with unfavorable outcome in various cancers, and evidence is accumulating that carcinogenesis possibly evolves from intracellular changes in response to induction of this enzyme. Today selective cyclooxygenase-2 inhibitors are being studied and used as complement in cancer treatment. This study examined the prognostic value of cyclooxygenase-2 expression in oral tongue squamous cell carcinoma (OTSCC).Expression of cyclooxygenase-2 was determined in biopsies from 76 stage matched patients with OTSCC by immunohistochemistry between January 2000 and December 2004 in Stockholm, Sweden. Additionally, twelve samples taken after pre-operative radiotherapy were investigated.All OTSCC specimen expressed cyclooxygenase-2 by immunostaining. The cyclooxygenase-2 staining intensity increased significantly with more advanced stage (P=0.020). Fifty percent of the surgical specimen showed a decrease in immunostaining post-radiation (P=0.031). No association was found with survival.Cyclooxygenase-2 expression has limited prognostic value in OTSCC.

In a prospective multicenter study, 186 patients with squamous cell esophageal carcinoma, who after evaluation were considered suitable for surgery, were randomized to 4 treatment groups: Group 1, surgery alone; Group 2, pre-operative chemotherapy (cisplatin and bleomycin) and surgery; Group 3, pre-operative irradiation (35 Gy) and surgery; Group 4, pre-operative chemotherapy, radiotherapy, and surgery. Three-year survival was significantly higher in the pooled groups receiving radiotherapy as compared with the pooled groups not receiving radiotherapy. Comparison of the groups having pre-operative chemotherapy with those not having chemotherapy showed no significant difference in survival. Female patients had a significantly better survival than males. The results indicate that pre-operative irradiation had a beneficial effect on intermediate term survival, whereas the chemotherapy regime used did not influence survival.

In the county of Stockholm, between 1970 and 2002, we have previously reported a 3-fold parallel increase in the incidence of tonsillar squamous cell carcinoma (SCC) and the proportion of human papillomavirus (HPV) positive tonsillar SCC. Here, we have followed the above parameters in all patients (n = 120) diagnosed with tonsillar SCC during 2003-2007 in the same area, and also in correlation to our previous data. Ninety-eight pretreatment biopsies were available and presence of HPV DNA and HPV-16 E6 and E7 RNA were tested by polymerase chain reaction (PCR) and RT-PCR. Incidence data were obtained from the Swedish Cancer Registry. Data reported from 1970 to 2002 were also obtained for comparison. HPV DNA was present in 83 of 98 (85%) of the tonsillar SCC biopsies from 2003 to 2007 and 77 of these were HPV-16 positive. HPV-16 E6 and E7 RNA were found in 98% of 52 analyzed HPV-16 positive cases. The proportion of HPV-positive cancers had significantly increased both from 1970 to 2007 (p < 0.0001) as well from 2000 to 2007 (p < 0.01), with 68% (95% confidence interval (CI), 53-81) 2000-2002; 77% (95% CI, 63-87) 2003-2005; and 93% (95% CI, 82-99) 2006-2007. The incidence rate of HPV-positive tumors almost doubled each decade between 1970 and 2007, in parallel with a decline of HPV-negative tumors. In conclusion, the incidence of HPV-positive cancers is still increasing in the County of Stockholm, suggesting an epidemic of a virus-induced carcinoma, with soon practically all tonsillar SCC being HPV positive, as in cervical cancer.

Our aim was to map and compare genomic imbalances in human papillomavirus (HPV)-positive and -negative squamous cell carcinomas of the tonsil. Twenty-five primary carcinomas were analyzed by comparative genomic hybridization. Fifteen (60%) were found to be HPV-positive by PCR, and the majority were HPV-16. There were statistically significant differences in the distribution of DNA gains and losses between the HPV-positive and -negative samples. Eleven of 15 HPV-positive samples (73%) showed gain on chromosome 3q24-qter, while only 4/10 (40%) HPV-negative samples had the same gain (p = 0.049). Furthermore, 4/10 (40%) HPV-negative samples but no HPV-positive samples had gain on chromosome 7q11.2-q22 (p = 0.017). As expected, and similar to previous studies, patients with an HPV-positive tumor had a statistically significantly better disease-specific survival than patients with an HPV-negative tumor (p = 0.002). The most common changes, e.g., gain on 3q or 8q, loss on 11q or 13 and loss on chromosome 7q in HPV-negative tumors, did not have any influence on prognosis. However the number of cases in each subgroup was limited.

Background. To determine possible molecular markers for predicting radiosensitivity in squamous cell carcinoma, we have examined the relationship between pretreatment expression of the DNA damage recognition complex DNA-PK, its in vitro substrates, p53 and MDM2, local tumor control after radiotherapy (RT), and patient survival. Methods and Materials. Formalin-fixed tumor biopsy specimens from 79 previously untreated patients with tonsillar carcinoma were analyzed by immunohistochemical methods. Results. Tumors expressing high levels of Ku86 had better locoregional control in contrast to tumors expressing low levels of Ku86 (p = .023). Survival of patients with tumors expressing high levels of DNA-PKcs was significantly better than survival of patients with tumors expressing low levels of DNA-PKcs (p = .0024). p53 and MDM2 status alone did not correlate with survival of patients. However, patients with p53 tumors and high DNA-PKcs expression had significantly better survival than patients with p53+ tumors expressing low levels of DNA-PKcs (p = .0018). Furthermore, survival of patients with high expression of DNA-PKcs or Ku86 and low MDM2 levels was significantly better when compared with survival of patients with low DNA-PKcs or Ku86 and high MDM2 (p = .0017 and p = .0034, respectively). Conclusions. High expression of DNA-PKcs/Ku86 in combination with p53 negativity in tonsillar carcinoma correlates with better survival of patients. Identifying tumors with a phenotype predicting poor survival may be used to optimize treatment of patients with radioresistant tumors. © 2003 Wiley Periodicals, Inc. Head Neck 25: 313–321, 2003