Publications by authors named "Lauri Jouhi"

23 Publications

  • Page 1 of 1

Long-term Quality of Life After Treatment of Oropharyngeal Squamous Cell Carcinoma.

Laryngoscope 2020 Aug 25. Epub 2020 Aug 25.

Department of Otorhinolaryngology-Head and Neck Surgery, Turku University and Turku University Hospital, Turku, Finland.

Objectives: To analyze the long-term quality of life (QOL) among oropharyngeal squamous cell carcinoma (OPSCC) survivors.

Study Design: Retrospective chart analysis and patient response to European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core Module (EORTC QLQ-C30), Head and Neck Module (EORTC QLQ-H&N35), and M.D. Anderson Dysphagia Inventory (MDADI) survey questionnaires.

Methods: All survivors of OPSCC diagnosed and treated between 2000 and 2009 in Finland were included. There were 263 survivors (44.2% of all curatively treated patients), of which a total of 164 participated in this study (62.4%). Median follow-up was 11.79 years (range = 8.59-18.53 years, interquartile range [IQR] = 4.64 years). The mean age of the participants was 67.9 years (standard deviation = 8.0 years) at QOL follow-up.

Results: Most survivors reported a good QOL. The EORTC QLQ-C30 global health status median was 75.00 (IQR = 31.25). The single modality treatment group had significantly better QOL outcomes than the combined treatment group. Nonsmokers and previous smokers had significantly better QOL outcomes than patients who smoked at the time of diagnosis. A history of heavy alcohol use resulted in significantly worse QOL outcomes. The p16-positive cancer patients had significantly better QOL outcomes than p16-negative patients. Percutaneous endoscopic gastrostomy (PEG) tube-dependent patients reported a significantly worse QOL than patients without a PEG tube.

Conclusions: Long-term QOL in OPSCC survivors is generally good. In line with previous literature, single modality treatment was superior to combined treatment in long-term QOL outcomes, and it should be pursued whenever possible.

Level Of Evidence: 4 Laryngoscope, 2020.
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http://dx.doi.org/10.1002/lary.29042DOI Listing
August 2020

Expression and Role of E-Cadherin, β-Catenin, and Vimentin in Human Papillomavirus-Positive and Human Papillomavirus-Negative Oropharyngeal Squamous Cell Carcinoma.

J Histochem Cytochem 2020 09 14;68(9):595-606. Epub 2020 Aug 14.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Oropharyngeal squamous cell carcinoma (OPSCC) is subclassified by the World Health Organization into two different entities: human papillomavirus (HPV)-positive and HPV-negative tumors. HPV infection promotes the epithelial-to-mesenchymal transition (EMT) and transformation of keratinocyte stem cells into cancer stem cells. EMT is a crucial process in the carcinogenesis of epithelial-derived malignancies, and we aimed to study the role of its markers in OPSCC. This study consists of 202 consecutive OPSCC patients diagnosed and treated with curative intent. We examined E-cadherin, β-catenin, and vimentin expression using immunohistochemistry and compared these with tumor and patient characteristics and treatment outcome. We found that the cell-membranous expression of β-catenin was stronger in HPV-positive than in HPV-negative tumors, and it was stronger in the presence of regional metastasis. The stromal vimentin expression was stronger among HPV-positive tumors. A high E-cadherin expression was associated with tumor grade. No relationship between these markers and survival emerged. In conclusion, β-catenin and vimentin seem to play different roles in OPSCC: the former in the tumor tissue itself, and the latter in the tumor stroma. HPV infection may exploit the β-catenin and vimentin pathways in carcinogenic process. More, β-catenin may serve as a marker for the occurrence of regional metastasis.
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http://dx.doi.org/10.1369/0022155420950841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469711PMC
September 2020

Challenges in diagnosing head and neck cancer in primary health care.

Ann Med 2021 12 5;53(1):26-33. Epub 2020 Aug 5.

Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: Early diagnosis of head and neck cancer (HNC) will improve patient outcomes. The low incidence of HNC renders its detection challenging for a general practitioner (GP) in primary health care (PHC).

Patients And Methods: To examine these challenges, our cohort consisted of all patients visiting PHC centres in the City of Helsinki in 2016. We chose 57 ICD-10 codes representing a sign or symptom resulting from a possible HNC and compared data for all new HNC patients.

Results: A total of 242,211 patients (499,542 appointments) visited PHC centres, 11,896 (5%) of whom presented with a sign or symptom possibly caused by HNC. Altogether, 111 new HNCs were diagnosed within the Helsinki area, of which 40 (36%) were referred from PHC. The median delay from the initial PHC visit to the referral to specialist care was 5 days, whereby 88% of patients were referred within one month.

Conclusions: Despite the low incidence of HNC and the large number of patients presenting with HNC-related symptoms, GPs working in PHC sort out potential HNC patients from the general patient group in most cases remarkably effectively. KEY MESSAGES For every head and neck cancer (HNC) patient encountered in the primary health care, a general practitioner (GP) will meet approximately 6000 other patients, 100 of whom exhibit a sign or a symptom potentially caused by a HNC. Despite the low incidence of HNC, GPs referred patients to specialist care effectively, limiting the median delay from the initial appointment to referral to only 5 days.
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http://dx.doi.org/10.1080/07853890.2020.1802060DOI Listing
December 2021

MRI correlates to histopathological data in oral tongue squamous cell carcinoma diagnostics.

Acta Odontol Scand 2020 Jul 11:1-6. Epub 2020 Jul 11.

HUS Medical Imaging Center, Department of Radiology, Helsinki University Hospital, Helsinki, Finland.

Objectives: The purpose of this study was to compare magnetic resonance imaging (MRI) maximum tumor diameter and depth of invasion with histopathology in oral tongue squamous cell carcinoma (OTSCC) patients in our Institute. Another objective was to compare recorded nodal status between MRI and histology.

Material And Methods: MRI and pathological records of 45 patients diagnosed with T1-T3 OTSCC were reviewed retrospectively. Maximum tumor diameter and depth of invasion were measured and rechecked by oral radiologist and pathologist. Nodal status was recorded from both MRI and histopathology. Correlation analyses were performed using Pearson's correlation.

Results: Both maximum tumor diameter and depth of invasion correlated significantly between MRI and histology ( = 0.874,  < .001;  = 0.898,  < .001). Significant correlation was found between MRI and pathological dimensions in the MRI-based T-staged subgroups of T2 and T3 but not in T1. MRI sensitivity for detecting pathologically positive nodes was 60%. MRI specificity for detecting pathologically negative nodes was 83%. Moderate correlation was found between MRI and histological nodal status ( = 0.44,  = .003).

Conclusions: MRI tumor dimensions correlate with histopathological data in OTSCC. Based on our Finnish patient material and results, MRI serves as an accurate tool in supporting OTSCC patient treatment in our Institute.
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http://dx.doi.org/10.1080/00016357.2020.1789736DOI Listing
July 2020

In HPV-negative oropharyngeal squamous cell carcinoma, elevated toll-like receptor 2 immunoexpression may increase the risk of disease-specific mortality.

Oral Oncol 2020 08 11;107:104778. Epub 2020 May 11.

Department of Pathology, University of Helsinki, HUSLAB and Helsinki University Hospital, P.O. Box 21, 00014 Helsinki, Finland; Research Programs Unit, Translational Cancer Medicine, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland; Department of Oral Pathology and Radiology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland.

Objectives: In oropharyngeal squamous cell carcinoma (OPSCC), toll-like receptors (TLR) 5 and 7 associate with the tumor's human papilloma virus (HPV) status (Jouhi et al., 2017). TLR 2, on the other hand, has been linked to head and neck squamous cell carcinoma (HNSCC), and to oral carcinogenesis (Farnebo et al., 2015; Binder Gallimidi et al., 2015). Here we investigated the presence of TLR 2 and 4 in HPV-positive and HPV-negative OPSCC, and their relationship to opportunistic oral pathogen Treponema denticola chymotrypsin-like protease (Td-CTLP) immunoexpression, clinical parameters, and patient outcome.

Materials And Methods: Clinicopathological data of 198 unselected consecutive OPSCC patients came from hospital registries. Immunoexpression of TLRs 2 and 4 we evaluated by immunohistochemistry, and earlier in this patient series we studied immunoexpression of Td-CTLP and HPV DNA, HPV mRNA, and p16 status.

Results: Immunoexpression of both TLRs 2 and 4 showed a significant association with HPV-status. Strong expression was associated with HPV-positivity and mild expression with HPV-negativity. Patients with strong TLR 2 immunoexpression in the HPV negative subgroup had significantly poorer 5-year DSS (58%) than did patients with mild TLR 2 expression (77%), and strong TLR 2 immunoexpression remained as an independent factor linked to increased disease mortality in the multivariable setting (P = 0.019). No association existed between TLR 2 or 4 and Td-CTLP expression.

Conclusion: Our results support the role of TLR 2 receptor as a possible target for development of therapeutics as earlier proposed (Farnebo et al., 2015). The involvement of Td and other oral pathogens in carcinogenesis of OPSCC, remains open and calls for further study.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104778DOI Listing
August 2020

Factors influencing patient and health care delays in Oropharyngeal Cancer.

J Otolaryngol Head Neck Surg 2020 Apr 23;49(1):22. Epub 2020 Apr 23.

Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, PO Box 263, FI-00029 HUS, Helsinki, Finland.

Background: The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing. Patients with HPV-associated and HPV-unassociated OPSCC differ in many aspects, which may also impact their diagnostic and management timelines. This study aims at studying the patient, primary health care (PHC) and specialist-care (SC) delays and possible differences between these two patient groups in seeking medical care.

Methods: We reviewed all new patients with OPSCC treated between 2016 and 2018 at our institute, which covers a referral area of 1.6 million people. We collected data on patients' symptoms and factors influencing why they sought medical care using a patient-reported questionnaire and hospital records. We compared delays based on patient and tumor characteristics.

Results: In our study population of 83 patients, the median patient delay was 30 days (range, 0-366), with a median PHC delay of 15 days (range, 0 days-2.5 years), and a median SC delay of 54 days (range, 12-231). The SC delay was further divided into diagnostic hospital delay and treatment delay, each with a median length of 16 days (range, 0-237) and 29 days (range, 0-73), respectively. Furthermore, we found that p16 status did not associate with delays. A longer patient delay associated with specific tumor factors, such as a larger primary tumor and a lower UICC 7th edition stage. Patients that had multiple visits or did not have a follow-up visit scheduled at the initial appointment had longer PHC delays. Treatment delay was significantly longer for patients scheduled for (chemo-)radiotherapy than for those undergoing surgery with or without (chemo-)radiotherapy.

Conclusions: Although delays remained short for the majority of OPSCC patients, long delays require further evaluation and improvement of management. Awareness of presenting symptoms among cancer risk patients and prompt referral practice or a follow-up visit at PHC represent key factors to shortening these delays. Ultimately, the causes for delays in SC appear multifactorial and require institutional quality control.
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http://dx.doi.org/10.1186/s40463-020-00413-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181590PMC
April 2020

Epstein-Barr virus (EBV) and polyomaviruses are detectable in oropharyngeal cancer and EBV may have prognostic impact.

Cancer Immunol Immunother 2020 Aug 20;69(8):1615-1626. Epub 2020 Apr 20.

Department of Pathology, University of Helsinki and HUS Helsinki University Hospital, P.O. Box 21, 00014 HUS, Helsinki, Finland.

Background: The etiological role of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is confirmed. However, the role of other oncoviruses in OPSCC is unknown.

Materials And Methods: A total of 158 consecutive OPSCC patients treated with curative intent were included. DNA extracted from tumor sections was used to detect Epstein-Barr virus (EBV), HPV, and the following polyomaviruses: John Cunningham virus (JCV), Simian virus 40 (SV40), and BK virus (BKV) with PCR. In addition, p16 expression was studied by immunohistochemistry, and EBV-encoded small RNA (EBER) transcripts were localized by in situ hybridization. The effect of viral status on overall survival (OS) and disease-free survival (DFS) was analyzed.

Results: A total of 94/158 samples (59.5%) were HPV-positive, 29.1% contained BKV DNA, 20.3% EBV DNA, 13.9% JCV DNA, and 0.6% SV40 DNA. EBER was expressed only in stromal lymphocytes adjacent to the tumor and correlated with HPV positivity (p = 0.026). p16 expression associated only with HPV. None of the three polyomaviruses had an impact on survival. Patients with EBER-positive but HPV-negative OPSCC had significantly poorer OS and DFS than those with HPV-positive OPSCC and slightly worse prognosis compared with the patients with EBER-negative and HPV-negative OPSCC.

Conclusion: Polyomaviruses are detectable in OPSCC but seem to have no impact on survival, whereas HPV was the strongest viral prognostic factor. EBER expression, as a sign of latent EBV infection, may have prognostic impact among patients with HPV-negative OPSCC. EBER analysis may identify a new subgroup of OPSCCs unrelated to HPV.
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http://dx.doi.org/10.1007/s00262-020-02570-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347695PMC
August 2020

Elevated TLR5 expression in vivo and loss of NF-κΒ activation via TLR5 in vitro detected in HPV-negative oropharyngeal squamous cell carcinoma.

Exp Mol Pathol 2020 06 30;114:104435. Epub 2020 Mar 30.

Department of Pathology, University of Helsinki, HUSLAB and Helsinki University Hospital, P. O. Box 21, 00014 Helsinki, Finland; Department of Surgery, University of Helsinki and Helsinki University Hospital, P. O. Box 20, FI-00014, Helsinki, Finland; Department of Oral Pathology and Radiology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland.

In oropharyngeal squamous cell carcinoma (OPSCC), the expression pattern of toll-like receptors (TLRs), in comparison between human papillomavirus (HPV)-positive and -negative tumors differs. TLRs control innate immune responses by activating, among others, the nuclear factor-κΒ (NF-κΒ) signaling pathway. Elevated NF-κΒ activity is detectable in several cancers and regulates cancer development and progression. We studied TLR5 expression in 143 unselected consecutive OPSCC tumors, and its relation to HPV-DNA and p16 status, clinicopathological parameters, and patient outcome, and studied TLR5 stimulation and consecutive NF-κB cascade activation in vitro in two human OPSCC cell lines and immortalized human keratinocytes (HaCat). Clinicopathological data came from hospital registries, and TLR5 immunoexpression was evaluated by immunohistochemistry. Flagellin served to stimulate TLR5 in cultured cells, followed by analysis of the activity of the NF-κB signaling cascade with In-Cell Western for IκΒ and p-IκΒ. High TLR5 expression was associated with poor disease-specific survival in HPV-positive OPSCC, which typically shows low TLR5 immunoexpression. High TLR5 immunoexpression was more common in HPV-negative OPSCC, known for its less-favorable prognosis. In vitro, we detected NF-κΒ cascade activation in the HPV-positive OPSCC cell line and in HaCat cells, but not in the HPV-negative OPSCC cell line. Our results suggest that elevated TLR5 immunoexpression may be related to reduced NF-κΒ activity in HPV-negative OPSCC. The possible prognosis-worsening mechanisms among these high-risk OPSCC patients however, require further evaluation.
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http://dx.doi.org/10.1016/j.yexmp.2020.104435DOI Listing
June 2020

High levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) in the serum are associated with poor prognosis in HPV-negative squamous cell oropharyngeal cancer.

Cancer Immunol Immunother 2019 Aug 25;68(8):1263-1272. Epub 2019 Jun 25.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and HUS Helsinki University Hospital, P.O.Box 263, 00029 HUS, Helsinki, Finland.

Background: An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC.

Materials And Methods: A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS).

Results: High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8-117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3-57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels.

Conclusion: Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.
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http://dx.doi.org/10.1007/s00262-019-02362-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682571PMC
August 2019

In situ hybridization for high-risk HPV E6/E7 mRNA is a superior method for detecting transcriptionally active HPV in oropharyngeal cancer.

Hum Pathol 2019 08 21;90:97-105. Epub 2019 May 21.

Department of Pathology, University of Helsinki and HUS Helsinki University Hospital, P.O.Box 21, FI-00014 HUS, Helsinki, Finland; Research Programs Unit, Translational Cancer Biology, University of Helsinki, P.O.Box 63, FI-00014, Helsinki, Finland.

Current human papillomavirus (HPV) detection methods in oropharyngeal squamous cell carcinoma (OPSCC) have varying sensitivity and specificity. We aimed to compare different HPV-detection methods against the test used in clinical practice, ie, p16 immunohistochemistry (IHC) and to evaluate whether another HPV-detection test additional to p16 IHC would be worthwhile in OPSCC specimens. The study cohort comprised 357 consecutive OPSCC patients during two time periods: 2000-2009 and 2012-2016. From tumor tissue slides, HPV mRNA via in situ hybridization (ISH), HPV DNA via ISH and HPV DNA via polymerase chain reaction (PCR) were detected. The results of these methods were compared with p16 IHC results. Additionally, clinicopathological factors were compared with the methods studied. The sensitivity of HPV mRNA ISH, HPV DNA ISH and HPV DNA PCR were 93.4%, 86.3%, and 83.5%, respectively. The corresponding specificity was 92.4%, 95.3%, and 89.1%, respectively. The negative predictive value for p16 IHC was highest (89.0%) when using mRNA ISH, and followed by DNA ISH (83.5%). ISH for high-risk HPV E6/E7 mRNA was found to be a highly specific and sensitive method for detecting HPV in OPSCC. As p16 protein may be overexpressed due to HPV-independent mechanisms, all p16 IHC-positive OPSCCs should be considered for retesting using mRNA ISH in order to verify transcriptionally active HPV. This is especially critical when considering de-escalated treatment approaches for patients with HPV-positive tumors and still maintaining favorable outcomes for this subgroup of patients.
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http://dx.doi.org/10.1016/j.humpath.2019.05.006DOI Listing
August 2019

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.

Tumour Biol 2019 Mar;41(3):1010428319840473

3 Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

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.
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http://dx.doi.org/10.1177/1010428319840473DOI Listing
March 2019

Management of clinically N0 neck in oropharyngeal carcinoma.

Eur Arch Otorhinolaryngol 2019 Apr 7;276(4):1205-1210. Epub 2019 Feb 7.

Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, P.O. Box 263, 00029 HUS, Helsinki, Finland.

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.
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http://dx.doi.org/10.1007/s00405-019-05314-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426801PMC
April 2019

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

Br J Cancer 2018 07 22;119(1):89-95. Epub 2018 Jun 22.

Department of Pathology, University of Helsinki, HUSLAB and Helsinki University Hospital, P.O. Box 21, 00014, Helsinki, Finland.

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.
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http://dx.doi.org/10.1038/s41416-018-0143-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035174PMC
July 2018

MMP-7 expression may influence the rate of distant recurrences and disease-specific survival in HPV-positive oropharyngeal squamous cell carcinoma.

Virchows Arch 2018 Jun 2;472(6):975-981. Epub 2018 May 2.

Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 263, 00029 HUS, Helsinki, Finland.

The objective of this study was to determine if matrix metalloproteinase-7 (MMP-7) expression is related to human papilloma virus (HPV) status, clinical parameters, and outcome in oropharyngeal squamous cell carcinoma (OPSCC). Tumor tissue specimens from 201 OPSCC patients treated with curative intent were available for immunohistochemistry, and the samples were stained with monoclonal MMP-7 antibody. All the patients were followed up at least 3 years or until death. MMP-7 expression did not differ between HPV-positive and HPV-negative patients. MMP-7 was not prognostic among patients with HPV-negative OPSCC. In the HPV-positive subgroup, patients with moderate, high, or very high MMP-7 expression had significantly worse 5-year disease-specific survival (DSS) (56.6%) than patients with absent, or low MMP-7 expression (77.2%), and MMP-7 expression appeared as a prognostic factor in the multivariate analysis. In addition, among HPV-positive OPSCC with moderate, high, or very high MMP-7 expression, the 5-year distant recurrence-free survival was significantly lower (69.6%) than in those who had low or absent MMP-7 expression (97.5%). Our results suggest that among HPV-positive OPSCC patients, high MMP-7 expression is related to worse 5-year DSS and increased rate of distant recurrences.
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http://dx.doi.org/10.1007/s00428-018-2365-6DOI Listing
June 2018

Expression of hormone receptors in oropharyngeal squamous cell carcinoma.

Eur Arch Otorhinolaryngol 2018 May 26;275(5):1289-1300. Epub 2018 Mar 26.

Department of Pathology, University of Helsinki, HusLab and Helsinki University Hospital, Haartmaninkatu 3, P.O. Box 21, 00014, Helsinki, Finland.

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.
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http://dx.doi.org/10.1007/s00405-018-4949-9DOI Listing
May 2018

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

Acta Oncol 2018 Apr 17;57(4):541-551. Epub 2017 Nov 17.

a Department of Otorhinolaryngology-Head and Neck Surgery , University of Helsinki, Helsinki University Hospital , Helsinki , 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.
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http://dx.doi.org/10.1080/0284186X.2017.1400688DOI Listing
April 2018

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

Cancer Immunol Immunother 2017 Dec 30;66(12):1619-1629. Epub 2017 Aug 30.

Pathology, University of Helsinki, HUSLAB, and Helsinki University Hospital, P.O Box 21, 00014 University of Helsinki, Helsinki, Finland.

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.
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http://dx.doi.org/10.1007/s00262-017-2054-3DOI Listing
December 2017

Changing trends in the management of the neck in oropharyngeal squamous cell carcinoma.

Head Neck 2017 07 2;39(7):1412-1420. Epub 2017 May 2.

Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 263, FI-00029 HUS, Helsinki, Finland.

Background: Treatment for oropharyngeal squamous cell carcinoma (SCC) has changed toward a more oncologic approach. We evaluated treatment of the neck, the incidence of regional recurrences, and factors associated with regional recurrence during the treatment approach transition period in patients with regional lymph node metastasis.

Methods: All patients with oropharyngeal SCC diagnosed at the Helsinki University Hospital during 2000-2009 were analyzed for clinicopathological factors, treatment, p16 expression, and regional recurrence.

Results: Altogether, 169 patients had a complete response, and among them regional recurrence occurred in 5 patients (4.7%) treated with surgery ± radiotherapy (RT) or chemoradiotherapy (CRT) and in 2 patients (3.2%) treated with RT or CRT ± surgery. All these 7 patients had N2b disease or higher, and 5 of them had regional recurrence in the contralateral side of the neck.

Conclusion: The incidence of regional recurrence was low, and remained unchanged despite the increased use of RT or CRT ± surgery. Treatment and follow-up of the contralateral neck warrants special attention in patients with advanced neck disease (≥N2b).
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http://dx.doi.org/10.1002/hed.24781DOI Listing
July 2017

Is p16 an adequate surrogate for human papillomavirus status determination?

Curr Opin Otolaryngol Head Neck Surg 2017 Apr;25(2):108-112

aDepartment of Otorhinolaryngology - Head and Neck Surgery bDepartment of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland cDivision of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Purpose Of Review: In head and neck cancer management, immunoexpression of protein p16 is widely used as a surrogate marker for human papillomavirus (HPV) positivity due to challenges of direct HPV testing. Previously p16 has been reported to have good sensitivity but only moderate specificity in HPV-status determination. The aim of this review is to evaluate the existing information on sensitivity and specificity of p16 immunohistochemistry (IHC) in HPV-status determination among the recent studies.

Recent Findings: We searched the time period from October 2014 to April 2016 and included 28 studies (a total of 31 analyses), which reported both p16 and HPV status in their series. The sensitivity of p16 in HPV determination ranged between 28.2 and 100.0%. The mean and median sensitivities were 90.5 and 95.4%, respectively. The specificity ranged between 31.1 and 100.0%. The mean and median specificities were 83.3 and 87.3%, respectively.

Summary: Our review presents current information on the feasibility of p16 IHC in HPV status determination, which is in line with previous studies. Patients with HPV-positive tumors can be identified with p16 IHC, but a risk for misclassification of HPV-negative tumors as HPV positive exists. This fact has to be taken into consideration if HPV status will influence treatment planning.
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http://dx.doi.org/10.1097/MOO.0000000000000341DOI Listing
April 2017

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

Tumour Biol 2015 Sep 5;36(10):7755-64. Epub 2015 May 5.

Department of Pathology and Oral Pathology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, P.O. Box 21, FI-00014, Helsinki, Finland.

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.
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http://dx.doi.org/10.1007/s13277-015-3494-zDOI Listing
September 2015

The expression of Toll-like receptors 2, 4, 5, 7 and 9 in Merkel cell carcinoma.

Anticancer Res 2015 Apr;35(4):1843-9

Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Department of Oral Pathology, University of Helsinki, Helsinki, Finland.

Aim: We sought to clarify whether the expression of toll-like receptors (TLR) in Merkel cell carcinoma (MCC) is linked to tumor and patient characteristics, especially the presence of Merkel cell polyoma virus (MCV).

Materials And Methods: The study comprised of 128 patients with data on Merkel cell polyomavirus (MCV) status and clinical features were included in the study. Immunohistochemistry for TLR expression was performed on tissue microarray (TMA) slides.

Results: TLR 2, 4, 5, 7 and 9 expression was noted in most of the tumor specimens. Decreased expression of TLR 9 correlated strongly with MCV positivity. Cytoplasmic TLR 2 expression correlated with small tumor size, while nuclear TLR 2 and TLR 5 expressions with larger tumors. Increased nuclear TLR 4 expression and decreased TLR 7 expression were associated with older age.

Conclusion: TLR 2, 4, 5, 7 and 9 appear to reflect certain clinicopathological variables and prognostic markers of MCC tumors.
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April 2015

Different Toll-Like Receptor Expression Patterns in Progression toward Cancer.

Front Immunol 2014 15;5:638. Epub 2014 Dec 15.

Department of Pathology and Oral Pathology, Haartman Institute, Institute of Dentistry and HusLab, University of Helsinki and Helsinki University Hospital , Helsinki , Finland.

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http://dx.doi.org/10.3389/fimmu.2014.00638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266018PMC
January 2015

Predictive role of Toll-like receptors 2, 4, and 9 in oral tongue squamous cell carcinoma.

Oral Oncol 2015 Jan 26;51(1):96-102. Epub 2014 Sep 26.

Department of Pathology, Haartman Institute, University of Helsinki, P.O. Box 21, Haartmaninkatu 3, FI-00014 University of Helsinki, Helsinki, Finland; Department of Pathology, HUSLAB, Helsinki University Central Hospital, P.O. Box 400, Haartmaninkatu 3, FI-00029 HUS, Helsinki, Finland. Electronic address:

Objectives: The clinical behavior of oral tongue squamous cell carcinoma (OTSCC) can be unpredictable, and even small tumors may behave aggressively. Toll-like receptors (TLRs) are pattern-recognition molecules involved in innate immunity, and they are also expressed in many types of cancer. TLRs play an apparently pivotal role in some cancers related to tumor progression and, conversely, cancer inhibition, however their role in oral cancer is unclear. We therefore studied the expression of TLR-2, -4, -5, -7, and -9 in early-stage OTSCC.

Materials And Methods: Tissue microarray technique and immunohistochemistry was employed to define the expression of TLRs from the tumors of 73 consecutive patients with Stage I-II OTSCC. Immunoexpression scores were compared with patient and tumor related characteristics and survival.

Results: All TLRs were expressed in OTSCC tissue. High/strong TLR-2, -4, and -9 expression correlated with deeper tumor invasion. Cytoplasmic TLR-2 and -4 also correlated significantly with higher tumor grade, whereas high TLR-5 expression associated with lower tumor grade. High expression of TLR-9 correlated with advanced tumor size. Negative or mild TLR-5 expression predicted poor disease-specific survival.

Conclusion: All the studied TLRs showed high expression in early-stage OTSCC. More importantly, TLR-2, -4, and -9 seemed to predict invasive tumor growth.
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http://dx.doi.org/10.1016/j.oraloncology.2014.08.017DOI Listing
January 2015