Psychosocial factors and patient and healthcare delays in large (class T3-T4) oral, oropharyngeal, and laryngeal carcinomas.

BACKGROUND: Psychosocial factors and socioeconomic status have been associated with incidence, survival, and quality of life among patients with head and neck cancer. We investigated the association between different psychosocial factors, socioeconomic status, and patient delays in T3-T4 oral, oropharyngeal, and laryngeal cancer. PATIENTS AND METHODS: We conducted a nationwide prospective questionnaire-based study (n = 203) over a 3-year period. RESULTS: We found no association between psychosocial factors (depression, social isolation, loneliness, and cynical hostility) and patient delay. Depression was three times more common among head and neck cancer patients compared with the general Finnish population. Head and neck cancer patients had lower educational levels and employment status, and were more often current smokers and heavy drinkers. CONCLUSIONS: Although we found no association between patient delay and psychosocial factors, patients diagnosed with a large head and neck cancer appeared to have a lower socioeconomic status and higher risk for developing depression, which should be considered in clinical practice.

PET-CT detection of local residual laryngeal carcinoma after definitive (chemo)radiotherapy.

BACKGROUND: Positron emission tomography and computed tomography (PET-CT) is currently recommended in evaluating the treatment response after (chemo)radiotherapy ([C]RT). In the larynx, post-treatment changes and physiological uptake make image interpretation more challenging compared to other head and neck sites. Previous research has not addressed imaging factors specifically in the larynx that would help in distinguishing the residual disease and explain the unique challenges of that anatomic area. The study cohorts are small and heterogenous. Our objective was to investigate the ability of PET-CT in diagnosing local residual laryngeal carcinoma, and to uncover imaging factors that could be used in differentiating the residual disease from post-treatment and physiological changes. In the same study cohort, we also aimed to uncover prognostic factors for local residual or recurrent disease. METHODS: Our retrospective study cohort included 73 patients with T2-T4 laryngeal carcinoma undergoing (C)RT with curative intention, and post-treatment non-contrast-enhanced PET-CT at 2-6 months. Findings were compared between local residual and non-residual disease. Local residual disease was defined as a persistent tumor growth with no evidence of remission in between, confirmed by biopsy, and evident within 6 months from the end of RT. PET-CT was evaluated using a 3-step scale: negative, equivocal, and positive. RESULTS: Nine (12%) had a local residual tumor and 11 (15%) developed local recurrence, based on the biopsy. The median follow-up of surviving patients was 64 months (range, 28-174). In univariate analysis, primary tumor diameter greater than 2.4 cm (median value), and vocal cord fixation were prognostic for local residual or recurrent disease. Sensitivity, specificity, PPV, and NPV were 100%, 75%, 36%, and 100%, respectively, when the equivocal interpretation was grouped with the positive interpretation. All local residuals, and 28% (18/64) non-residuals, had a primary tumor area SUVmax of over 4.0 (p < 0.001). CT showed a persistent mass at the primary tumor area in 56% of residuals, and in 23% of non-residuals (p > 0.05). By combining SUVmax>4.0 and mass, specificity improved to 91%. CONCLUSIONS: NPV of post-treatment PET-CT in laryngeal carcinoma is high, but equivocal and positive results have low PPV and require further diagnostics. All local residuals had SUVmax over 4.0. The combination of SUVmax over 4.0 and mass on CT increased specificity, but the sensitivity was low.

Tumour-infiltrating lymphocytes in oropharyngeal cancer: a validation study according to the criteria of the International Immuno-Oncology Biomarker Working Group.

BACKGROUND: The evaluation of immune response can aid in prediction of cancer behaviour. Here, we assessed the prognostic significance of tumour-infiltrating lymphocytes (TILs) in oropharyngeal squamous cell carcinoma (OPSCC). METHODS: A total of 182 patients treated for OPSCC were included in this study. Assessment of TILs was conducted on tumour sections stained with standard haematoxylin and eosin (HE) staining. We used the scoring criteria proposed by the International Immuno-Oncology Biomarker Working Group. RESULTS: The multivariable analysis showed that TILs associated with disease-specific survival with a hazard ratio (HR) of 2.13 (95% CI 1.14-3.96; P = 0.017). Similarly, TILs associated significantly with overall survival with HR of 1.87 (95% CI 1.11-3.13; P = 0.018). In a sub-analysis of HPV-positive and HPV-negative cases separately, TILs showed a significant prognostic value in both groups (P < 0.05). CONCLUSION: The evaluation of TILs as proposed by the International Immuno-Oncology Biomarker Working Group is a simple and promising method in prediction of survival of OPSCC. It is easily applicable and after further validation can be implemented in the routine pathological report as a basic immune parameter.

IgG4-positive plasma cells in nonspecific sialadenitis and sialolithiasis.

Chronic sclerosing sialadenitis is commonly regarded as a manifestation of IgG4-related disease. We previously found that a high IgG4 expression or IgG4-related disease could accompany nonspecific sialadenitis, whereas chronic sclerosing sialadenitis was not directly associated with IgG4-related disease. Our previous findings lead us to hypothesize that these inflammatory conditions of the submandibular gland signify a continuous progression of disease rather than different disease entities. We, therefore, aimed to determine the presence of IgG4-positivity and genuine IgG4-related disease in a cohort of 165 submandibular gland specimens from patients who underwent surgery due to chronic nonspecific sialadenitis or sialolithiasis. To do so, we re-evaluated histopathological features and divided samples into three groups: (A) nonspecific sialadenitis without known sialolithiasis, (B) sialadenitis with sialolithiasis, and (C) sialolithiasis without sialadenitis. We performed immunohistochemical staining for IgG4, IgG, and CD31, and assessed the Boston consensus statement criteria for IgG4-related disease in IgG4-positive samples. We also reviewed patient records and supplemented follow-up data with a questionnaire among patients with IgG4-positive samples. IgG4-positive plasma cells (range 1-344) were found in 131 samples. Among these, 19 samples were classified as IgG4-positive (≥70 IgG4-positive plasma cells/high-power field). Two IgG4-positive samples were histologically highly suggestive of IgG4-related disease, but only one had a clinically confirmed diagnosis of IgG4-related disease. Our results indicate that patients with sialadenitis and sialolithiasis often present with IgG4-positive lymphoplasmacytic infiltrates, but exceedingly rarely present with genuine IgG4-related disease. In sialolithiasis without sialadenitis, IgG4-positive plasma cells are often absent or appear in small numbers. These results support our hypothesis of a continuum of disease, and indicate that progressive inflammation of the submandibular gland leads to the development of more specific pathological features over time.

The presence of herpesviruses in malignant but not in benign or recurrent pleomorphic adenomas.

BACKGROUND: The etiology of salivary gland tumors is mainly unknown. The anatomical location of the salivary glands, with the mucosal pathway to the oral cavity and its rich microbiome, raises the question of potential viral background. OBJECTIVE: This study focuses on the potential presence of herpes-, polyoma- and parvoviruses in pleomorphic adenoma (PA), recurrent pleomorphic adenoma (RPA) and carcinoma ex pleomorphic adenoma (CaxPA). METHODS: Thirty different viruses were analyzed by PCR-based assays in 68 formalin-fixed paraffin-embedded salivary gland tumors (25 PA, 31 RPA and 12 CaxPA). RESULTS: Virus DNA was detected altogether in 19/68 (28%) tumor samples. Human herpesviruses 6B and 7 (HHV-6B and HHV-7) and Epstein-Barr virus (EBV) were frequently and almost exclusively found in CaxPA (5/12, 7/12, and 3/12, respectively). Within the 7 CaxPA that were virus-positive, 3 samples contained 3, and 1 sample even 4, different viruses. Infrequent viral positivity was shown for parvovirus B19 and cutavirus, as well as Merkel cell and Malawi polyomaviruses. CONCLUSIONS: Our unexpected finding of herpesvirus DNA almost exclusively in CaxPA tissues deserves further in-depth studies.

Sclerosing sialadenitis of the submandibular gland is rarely an immunoglobulin G4-related disease in the Finnish population.

Chronic sclerosing sialadenitis may represent one of many manifestations of an immunoglobulin G4-related disease. However, existing studies typically consist of small patient cohorts rarely conducted in Western populations. The clinical behavior of chronic sclerosing sialadenitis, including follow-up data, warrants further study. Thus, we aimed to determine whether chronic sclerosing sialadenitis always presents as IgG4-related disease or associates with autoimmune diseases and to determine which additional examinations patients may require. Between 2000 and 2017, 51 patients undergoing submandibular gland resection within the Helsinki University Hospital area were diagnosed with chronic sclerosing sialadenitis. We re-evaluated all specimens and performed immunostaining for IgG4. IgG and CD31 stainings were performed for IgG4-positive specimens. IgG4-related disease diagnosis was defined by the Boston consensus statement criteria. We revised clinical data, distributing a follow-up questionnaire to patients to register symptoms of IgG4-related disease or autoimmune disease during follow-up. The chronic sclerosing sialadenitis criteria were fulfilled in 34 patients, whereby 17 were diagnosed as non-sclerosing chronic sialadenitis. In 19 cases, a sialolith associated with a salivary gland lesion. In total, 12 of 51 cases were recognized as IgG4-positive, while two met the criteria for IgG4-related disease. These two cases belonged to the non-sclerosing chronic sialadenitis group, and both involved other organs. The histopathological features between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis overlapped regarding the degree of fibrosis and inflammatory infiltrates. In the Finnish population, chronic sclerosing sialadenitis of the submandibular gland does not appear to present as IgG4-related disease. Non-sclerosing chronic sialadenitis can associate with IgG4-related disease. A histopathological distinction between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis is not always unequivocal and the presence of a sialolith does not exclude IgG4-positivity. Therefore, immunostaining for IgG4 should be performed when dense plasma cell infiltration is present in either non-sclerosing chronic sialadenitis or chronic sclerosing sialadenitis.

The expression and prognostic value of stem cell markers Bmi-1, HESC5:3, and HES77 in human papillomavirus-positive and -negative oropharyngeal squamous cell carcinoma.

Human papillomavirus is detected in over 50% of oropharyngeal squamous cell carcinomas. Human papillomavirus-positive oropharyngeal squamous cell carcinomas differ from human papillomavirus-negative tumors, and both expression patterns are classified as distinct entities. The Bmi-1 oncogene is a well-known member of the mammalian polycomb-group family. HESC5:3 and HES77 are newly developed monoclonal antibodies produced against undifferentiated embryonic stem cells. Our aim was to explore their roles in both human papillomavirus-positive and -negative oropharyngeal squamous cell carcinomas. Our cohort comprised 202 consecutive oropharyngeal squamous cell carcinoma patients diagnosed and treated with curative intent. We used tissue microarray tumor blocks to study the immunohistochemical expression of Bmi-1, HESC5:3, and HES77. We compared the expressions of these stem cell markers with p16 immunoexpression and human papillomavirus status, as well as with other characteristics of the tumor, and with patients' clinical data and follow-up data. Human papillomavirus- and p16-positive tumors expressed less Bmi-1 and more HESC5:3 than the negative tumors. HES77 expression was high in human papillomavirus-positive oropharyngeal squamous cell carcinoma, but it did not correlate with p16 positivity. In our multivariable model, Bmi-1 and HESC5:3 were still associated with human papillomavirus, but the association between human papillomavirus and HES77 remained absent. In conclusion, Bmi-1, HESC5:3, and HES77 may have a different role in human papillomavirus-positive and human papillomavirus-negative tumors. There was no correlation between Bmi-1, HESC5:3, and HES77 expression and survival.

Management of clinically N0 neck in oropharyngeal carcinoma.

PURPOSE: Only a minority of patients with oropharyngeal squamous cell carcinoma (OPSCC) are diagnosed without regional metastasis (cN0). Studies focusing on the management of cN0 neck in OPSCC are scarce. METHODS: We reviewed all OPSCC patients treated at our institution with cN0 neck between 2000 and 2009. The treatment of neck and pattern of regional control was analyzed. Median follow-up was 5 years (range 3.5-9.0) or until death. RESULTS: Of the total 313 OPSCC patients treated within the period, 56 (18%) presented with cN0 neck. Of them, 51 (91%) received completed treatment with curative intent: 46 (90%) underwent elective neck treatment with either neck dissection ± (chemo)radiotherapy (C)RT (n = 23) or (C)RT (n = 23). A regional recurrence occurred in three patients (6%) and they all had a p16-negative soft palate midline primary tumor. Two of these patients had received RT on the neck. CONCLUSIONS: While the overall prognosis of OPSCC is generally favorable and regional recurrences are infrequent, soft palate tumors, that are usually p16 negative, may form an subgroup warranting more aggressive treatment despite the clinical appearance of early stage.

Total laryngopharyngectomy with circumferential reconstruction: Helsinki institutional study.

PURPOSE: Surgical complications after total laryngopharyngectomy (TLP) are common, reconstruction is challenging, and patients often lose their ability to swallow and speak. To evaluate these aspects, we analysed outcome after TLP. METHODS: We reviewed all patients who underwent TLP and subsequent circumferential pharyngeal reconstruction through 2004-2017 at the Helsinki University Hospital. RESULTS: For the 26 eligible patients, TLP was the primary treatment for 11 and salvage surgery for 15, followed by reconstruction with free flaps in 22 patients and pedicled flaps in 4. An early (≤ 30 days) pharyngocutaneous fistula developed in seven patients (27%; median time 13 days; range 6-26), and a late (> 30 days) fistula in five patients (19%; median time 370 days; range 46-785). In addition, ten patients (39%) developed an oesophageal stricture. Four patients (15%) resumed full oral feeding. A speech prosthesis was inserted for 15 patients (58%) and most of them could produce intelligible speech. We found acceptable survival figures for patients undergoing TLP both as a primary treatment and as salvage procedure: the overall survival at 1 year was 82% and 67%, and at 5 years 33% and 27%, respectively. Disease-specific survival at 1 year was 90% and 70%, and that at 5 years was 45% and 43%, respectively. CONCLUSIONS: Despite fair survival, TLP carries a high risk for postoperative complications with limited functional outcome, thus necessitating cautious patient selection and surgical experience.

Treponema denticola chymotrypsin-like protease as associated with HPV-negative oropharyngeal squamous cell carcinoma.

BACKGROUND: An opportunistic oral pathogen, Treponema denticola (Td), has been linked to orodigestive carcinogenesis, but its role in oropharyngeal squamous cell carcinoma (OPSCC) has remained open. We evaluated the presence of Td chymotrypsin-like protease (Td-CTLP) in a series of 201 unselected consecutive OPSCC patients, and the relation of the Td-CTLP to human papillomavirus (HPV) status, to expression of toll-like receptors (TLR) 5, 7, and 9, and to clinical parameters and patient outcome. METHODS: Clinicopathological data came from hospital registries. The expression of cell surface-bound Td-CTLP was evaluated by immunohistochemistry. Immunoexpression of TLRs 5, 7, and 9, and HPV status we studied earlier in this patient series. RESULTS: We detected Td-CTLP in 81% of the OPSCC, and especially in HPV-negative tumours (48% of all OPSCCs). Among the HPV-positive tumours (52% of all OPSCCs), low Td-CTLP expression associated with low TLR 5 and high TLR 7 expression. Among those HPV-negative, higher TLR 5 and lower TLR 7 expression associated with high Td-CTLP expression. Strong Td-CTLP expression associated with poor disease-specific survival, but no similar association among HPV-positive and HPV-negative subgroups emerged. CONCLUSIONS: Td-CTLP was highly expressed in OPSCC and was associated with the HPV status of tumour tissue.

Epidemiological and treatment-related factors contribute to improved outcome of oropharyngeal squamous cell carcinoma in Finland.

BACKGROUND: Treatment for oropharyngeal squamous cell carcinoma (OPSCC) has changed, as the proportion of human papilloma virus (HPV)-related disease has increased. We evaluated nationwide information on its management and outcome during the treatment paradigm change period. METHODS: We included all patients diagnosed and treated for OPSCC at the five Finnish university hospitals from 2000 to 2009. Patient records and pathology registries provided the clinicopathological data. p16 staining was performed on primary tumor samples of patients who had received treatment with curative intent. RESULTS: A total of 674 patients were diagnosed and treated for OPSCC and the incidence increased along the study period. Of the evaluable tumors 58.5% were p16-positive and the number of p16-positive tumors increased along the years. The treatment was given with curative intent for 600 patients and it was completed in 564. Of them, 47.9% underwent primary surgery and 52.1% received definitive oncological treatment. Also, the treatment protocol changed towards a more oncological approach. Among patients treated with curative intent the five-year overall, disease-specific and disease-free survival rates were 60.1, 71.5 and 57.0%. In multivariate analysis, p16-positivity seemed to relate to reduced disease mortality in lateral and anterior-wall disease. Depending on primary tumor localization, also sex, classes T3-4, presence of regional metastasis and radiotherapy modality had an association with disease mortality. CONCLUSION: The incidence of p16-positive OPSCC and delivery of definitive oncological treatment increased in Finland during the study period. An improved survival outcome compared with the previous nationwide investigation was observed in this subset of patients.

Expression of hormone receptors in oropharyngeal squamous cell carcinoma.

OBJECTIVES: Hormone receptors play an important role in many types of cancers. Alongside factors associated with human papillomavirus (HPV) infection, hormonal receptors may impact the tumorigenesis of oropharyngeal cancer. MATERIALS AND METHODS: This study consists of 199 consecutive oropharyngeal squamous cell carcinoma (OPSCC) patients diagnosed and treated with a curative intent. We examined androgen (AR), estrogen (ER; both alpha and beta), and progesterone receptor (PR) expressions using immunohistochemistry comparing tumor and patient characteristics. RESULTS: AR was expressed in 16%, PR in 27% and ER-beta in 63% of the tumors. HPV- and p16-positive tumors expressed more AR and less PR than their negative counterparts. High PR expression was associated with poor disease-specific and locoregional recurrence-free survival. CONCLUSION: AR, PR, and ER-beta are expressed in OPSCC, and AR and PR expressions are associated with HPV and p16 status. Furthermore, PR appears to have prognostic significance. This may allow us to investigate the role of anti-hormone receptors in the treatment of OPSCC.

Toll-like receptor 5 and 7 expression may impact prognosis of HPV-positive oropharyngeal squamous cell carcinoma patients.

A large subset of oropharyngeal squamous cell carcinomas (OPSCCs) is associated with HPV infection and has better outcome than non-viral-related tumors. Various malignancies also carry a role for TLRs, key activators of inflammation and innate immunity. We examined the expression of TLRs in OPSCC, and their association with HPV status and treatment outcome. TLR 5, 7, 9, and p16 were studied by immunohistochemistry and HPV status was detected with in situ hybridization in 202 tumors of consecutively treated OPSCC patients using tissue microarray method. The relations between TLR expression and HPV status, p16 expression, clinicopathological factors, and survival were analyzed. TLR 5, 7, and 9 expression patterns differed between HPV-positive and -negative tumors, and they were statistically significantly associated with history of smoking, heavy drinking, tumor site, grade, size (T), metastasis (N), and stage. Moreover, in HPV-positive tumors the expression of TLR 5 and 7 correlated with tumor recurrence. After adjustment, among HPV-positive OPSCC patients, high TLR 5 and low TLR 7 expression were associated with poor disease-specific survival. Our results indicate that TLR 5 and 7 may have a role in the prognostication of HPV-positive OPSCC, however, further studies are needed to clarify the comprehensive role of these TLRs in OPSCC.

Prospective experience of percutaneous endoscopic gastrostomy tubes placed by otorhinolaryngologist-head and neck surgeons: safe and efficacious.

Percutaneous endoscopic gastrostomy (PEG) is often the treatment of choice in head and neck cancer (HNC) patients needing long-term nutritional support. Prospective studies on PEG tube placement in an otorhinolaryngologist service are lacking. At our hospital, otolaryngologist-head and neck (ORL-HN) surgeons-have performed PEG insertions for HNC patients since 2008. We prospectively analyzed 127 consecutive HNC patients who received their PEG tubes at the Department of Otorhinolaryngology-head and neck surgery, and evaluated the outcome of PEG tube insertions performed by ORL-HN surgeons. To compare time delays before and after, PEG placement service was transferred from gastrointestinal surgeons to ORL-HN surgeons, and we retrospectively analyzed a separate group of 110 HNC patients who had earlier received PEG tubes at the Department of Gastrointestinal Surgery. ORL-HN surgeons' success rate in PEG insertion was 97.6%, leading to a final prospective study group of 124 patients. Major complications occurred in four (3.2%): two buried bumper syndromes, one subcutaneous hemorrhage leading to an abscess in the abdominal wall, and one metastasis at the PEG site. The most common minor complication was peristomal granulomatous tissue affecting 23 (18.5%) patients. After the change in practice, median time delay before PEG insertion decreased from 13 to 10 days (P < 0.005). The proportion of early PEG placements within 0-3 days increased from 3.6 to 14.6% (P < 0.005). PEG tube insertion seems to be a safe procedure in the hands of an ORL-HN surgeon. Independence from gastrointestinal surgeons' services reduced the time delay and improved the availability of urgent PEG insertions.

Toll-like receptors 2, 4, and 9 in primary, metastasized, and recurrent oral tongue squamous cell carcinomas.

BACKGROUND: Toll-like receptors (TLRs) are pattern-recognizing proteins involved in innate immunity and they seem to regulate both cancer progression and inhibition. In oral cancer, TLR activation has been linked to invasion. To define the role of TLR-2, TLR-4, and TLR-9 in oral tongue squamous cell carcinoma (OTSCC), we studied their expression in vivo in OTSCC tumor samples, as well as in vitro in cell invasion model. METHODS: We used immunohistochemistry to compare the expression of TLR-2, TLR-4, and TLR-9 in 21 primary Stage I-II OTSCCs, neck metastases, and recurrent tumors. In addition, we used myoma organotypic invasion assay to evaluate the effect of GIT27 (4,5-dihydro-3-phenyl-5-isoxasoleaceticacid) on the invasion of the HSC-3 OTSCC cell line. RESULTS: TLR-2, TLR-4, and TLR-9 were expressed in most tumors. Nuclear TLR-2 expression occurred more often in primary tumors than in neck metastases or recurrent tumors of the neck, whereas nuclear TLR-4 expression and cytoplasmic TLR-9 expression were higher in primary tumors than in local recurrent tumors. GIT27 did not affect the invasion of HSC-3 OTSCC cells, but a myoma organotypic invasion assay revealed that the expression of TLR-2 and TLR-4 was stronger in deeper-invading cells. CONCLUSIONS: TLR-2, TLR-4, and TLR-9 were expressed in primary tumors, neck metastases as well as in recurrent tumors of OTSCC. Thus, these receptors seem to play a role in both the development and progression of tongue carcinoma. These TLRs may also contribute to the invasive potential of OTSCC.

Cancer of the tongue - early detection improves the prognosis.

Approximately 30 to 40% of all patients with tongue cancer still succumb to the disease in five years. Early diagnosis of the disease is of vital importance, because treatment will in that case cause considerably less harm. The diagnosis is confirmed with a histological specimen, which should be taken from every suspicious lesion, and can easily be taken under local anesthesia with a punch. Already when seeking treatment, as many as 25 % of patients with tongue cancer have neck metastases, which influence the prognosis. Heavy use of tobacco and alcohol are the most important risk factors of tongue cancer.

Expression of toll-like receptors in HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma--an in vivo and in vitro study.

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past decades in many western countries. This trend is mainly attributed to the human papillomavirus (HPV). Cancer-related actions of immunological defense systems are being intensively researched. Human toll-like receptors (TLRs) are a family of pattern recognition receptors that participate in the immunological defense against pathogens, but their actions are also linked to cancer. The expression of TLRs in cervical epithelium alters both during the clearance of HPV infection and the HPV-induced neoplasia, but the expression of TLRs has not been studied in OPSCC. Thirty-five paraffin-embedded, formalin-fixed, squamous cell carcinoma tissue specimens were analyzed for TLRs 2, 3, 4, 5, 7, and 9 and HPV and p16 statuses. The TLR 9 expression was lower in HPV-positive tumors compared with HPV-negative tumors. TLR 7 was expressed in all cancer specimens, but elevated expression was evident in HPV and/or p16-positive tumors. The majority of p16-positive tumors did not express TLR 5, whereas its expression was stronger in p16-negative tumors. The results of in vitro analysis of five human OPSCC cell lines and one human oral tongue squamous cell carcinoma cell line agree with the in vivo trends: low levels of TLR 5 and high levels of TLR 7 in p16-positive OPSCC. Overall, TLR 7 and 9 expression patterns are demonstrated here to relate to the HPV status in vivo and TLR 5 and 7 expression patterns to the p16 status in vivo and in vitro.

Toll-like receptors -4 and -5 in oral and cutaneous squamous cell carcinomas.

BACKGROUND: Oral squamous cell carcinoma (OSCC) has a worse prognosis than cutaneous squamous cell carcinoma (CSCC). Toll-like receptor- 4 (TLR-4) and TLR-5 are transmembrane proteins that recognize endogenous and microbial agents. Their activation has been connected to cancer invasion. OBJECTIVE: The aim was to study the expression of TLR-4 and TLR-5 in OSCC and CSCC samples, and the effects of TLR-5 ligand flagellin on the proliferation, migration, and invasion of different mucocutaneous cell lines in vitro. METHODS: Samples of early-stage tumors (T1-T2N0M0) from 63 patients with OSCC and CSCC were obtained, in addition to eight normal mucosa and skin tissues from healthy subjects. Oral-cavity-derived highly aggressive HSC-3, less invasive SAS, and HPV-transformed benign IHGK as well as C-ha-ras-transformed (HaCat) skin carcinoma II-4 and non-invasive A5 cell lines were used. Flagellin-induced mucocutaneous cell lines were compared by using BrdU-proliferation, scratch migration, and myoma organotypic invasion assays. RESULTS: TLR-4 expression was similar in OSCC and CSCC tumors. TLR-5 was more abundant in OSCC than in CSCC samples. Flagellin induced the proliferation of SAS, II-4 and A5, migration of IHGK, II-4 and A5, and the invasion of II-4 cells. It had no effect on HSC-3 cells. CONCLUSIONS: Flagellin, a TLR-5 agonist, induced the migration and invasion of less aggressive mucocutaneous cell lines, but it had no effect on the most invasive oral carcinoma cells. The more aggressive clinical behavior of OSCC compared to CSCC may partially be related to the differences in the expression of TLR-5 in these malignancies.

Toll-like receptor 9 mediates invasion and predicts prognosis in squamous cell carcinoma of the mobile tongue.

BACKGROUND: Toll-like receptor 9 (TLR9) is a cellular receptor, which recognizes bacterial and host-derived DNA. Stimulation of TLR9 induces cellular invasion via matrix metalloproteinase 13 (MMP-13). The aim of this study was to evaluate the role of TLR9 in invasion of oral tongue squamous cell carcinoma (OTSCC). METHODS: The effects of TLR9 ligands on oral squamous cell carcinoma cell lines were studied with invasion and migration assays, as well as in a myoma organotypic model. RESULTS: The TLR9 ligand, CpG-ODN, increased invasion and migration in OTSCC lines. These effects were reduced by TLR9 siRNA or inhibition with TLR9 antibodies. Immunohistochemical analysis of tissues from 195 patients with OTSCC revealed that TLR9 was expressed in 181/195 carcinomas. The expression of TLR9 was higher in the malignant cells than in the normal epithelium. High TLR9 expression was associated with high MMP-13 expression and poor differentiation. High TLR9 expression was also identified as an independent predictor of poor prognosis (HR 1.810, 95% CI [1.053-3.112]). CONCLUSION: Toll-like receptor 9 mediates OTSCC invasion and migration in vitro and is an independent prognostic factor of OTSCC. Inhibition of TLR9 may be a novel therapeutic opportunity in oral cancer.

[Necrotizing sialometaplasia]. / Nekrotisoiva sialometaplasia--suun tuumori ei ollutkaan syöpä.

Necrotizing sialometaplasia is a rare inflammatory condition clinically and histologically resembling a malignant tumor. The lesion is usually present on the palatal mucosa, and heals up without treatment during a couple of months. Differential diagnosis is essential in order to avoid excessive therapy. We describe a case where an oral tumor was not a cancer after all.