Publications by authors named "Alhadi Almangush"

45 Publications

Clinical significance of tumor-stroma ratio in head and neck cancer: a systematic review and meta-analysis.

BMC Cancer 2021 Apr 30;21(1):480. Epub 2021 Apr 30.

Institute of Biomedicine, Pathology, University of Turku and Turku University Hospital, Turku, Finland.

Background: The clinical significance of tumor-stroma ratio (TSR) has been examined in many tumors. Here we systematically reviewed all studies that evaluated TSR in head and neck cancer.

Methods: Four databases (Scopus, Medline, PubMed and Web of Science) were searched using the term tumo(u)r-stroma ratio. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were followed.

Results: TSR was studied in nine studies of different subsites (including cohorts of nasopharyngeal, oral, laryngeal and pharyngeal carcinomas). In all studies, TSR was evaluated using hematoxylin and eosin staining. Classifying tumors based on TSR seems to allow for identification of high-risk cases. In oral cancer, specifically, our meta-analysis showed that TSR is significantly associated with both cancer-related mortality (HR 2.10, 95%CI 1.56-2.84) and disease-free survival (HR 1.84, 95%CI 1.38-2.46).

Conclusions: The assessment of TSR has a promising prognostic value and can be implemented with minimum efforts in routine head and neck pathology.
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http://dx.doi.org/10.1186/s12885-021-08222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086072PMC
April 2021

Biomarkers for Immunotherapy of Oral Squamous Cell Carcinoma: Current Status and Challenges.

Front Oncol 2021 8;11:616629. Epub 2021 Mar 8.

Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Oral squamous cell carcinoma (OSCC) forms a major health problem in many countries. For several decades the management of OSCC consisted of surgery with or without radiotherapy or chemoradiotherapy. Aiming to increase survival rate, recent research has underlined the significance of harnessing the immune response in treatment of many cancers. The promising finding of checkpoint inhibitors as a weapon for targeting metastatic melanoma was a key event in the development of immunotherapy. Furthermore, clinical trials have recently proven inhibitor of PD-1 for treatment of recurrent/metastatic head and neck cancer. However, some challenges (including patient selection) are presented in the era of immunotherapy. In this mini-review we discuss the emergence of immunotherapy for OSCC and the recently introduced biomarkers of this therapeutic strategy. Immune biomarkers and their prognostic perspectives for selecting patients who may benefit from immunotherapy are addressed. In addition, possible use of such biomarkers to assess the response to this new treatment modality of OSCC will also be discussed.
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http://dx.doi.org/10.3389/fonc.2021.616629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982571PMC
March 2021

Back to basics: Hematoxylin and eosin staining is the principal tool for histopathological risk assessment of oral cancer.

Oral Oncol 2021 04 29;115:105134. Epub 2020 Dec 29.

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2020.105134DOI Listing
April 2021

Biopsy quality is essential for preoperative prognostication in oral tongue cancer.

APMIS 2021 Mar 28;129(3):118-127. Epub 2020 Dec 28.

Department of Pathology, University of Helsinki, Helsinki, Finland.

A role for incisional biopsy in preoperative prognostication is increasingly being advocated in oral tongue squamous cell carcinomas (OTSCC). Biopsies at two locations were compared, and prognostic factors in biopsies and their corresponding resections were evaluated. A total of 138 OTSCC biopsy slides from Finland and Saudi Arabia were compared for size (horizontal and vertical) and invasive front. The Finnish cases were assessed for tumor stroma ratio (TSR) and tumor-infiltrating lymphocytes (TILs) using light microscopy and digital image analysis assessment and compared. Furthermore, TSR, TILs, and previously analyzed budding and depth of invasion (BD) score in biopsies were compared with their evaluation in the corresponding resections. Fifty-nine percent of Finnish and 42% of Saudi Arabian biopsies were ≥ 5 mm deep, while 98% of Saudi Arabian and 76% of Finnish biopsies were ≥ 5 mm wide. Assessment of invasion front was possible in 72% of Finnish in comparison with 40% of Saudi Arabian biopsies. There was 86.8% agreement between TSR and 75% agreement between TIL evaluation using light microscopy and digital assessment. Significant agreement was obtained on comparing the TSR (p = 0.04) and BD (p < 0.001) values in biopsies and resections. Biopsies of ≥ 5 mm depth from representative OTSCC areas are essential for prognostic information. Clinical pathologists are advised to assess BD score and TSR for prognostic features in such biopsies.
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http://dx.doi.org/10.1111/apm.13104DOI Listing
March 2021

Comparison of nomogram with machine learning techniques for prediction of overall survival in patients with tongue cancer.

Int J Med Inform 2021 01 24;145:104313. Epub 2020 Oct 24.

Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; University of Turku, Institute of Biomedicine, Pathology, Turku, Finland; Department of Pathology, University of Helsinki, Helsinki, Finland; Faculty of Dentistry, University of Misurata, Misurata, Libya.

Background: The prediction of overall survival in tongue cancer is important for planning of personalized care and patient counselling.

Objectives: This study compares the performance of a nomogram with a machine learning model to predict overall survival in tongue cancer. The nomogram and machine learning model were built using a large data set from the Surveillance, Epidemiology, and End Results (SEER) program database. The comparison is necessary to provide the clinicians with a comprehensive, practical, and most accurate assistive system to predict overall survival of this patient population.

Methods: The data set used included the records of 7596 tongue cancer patients. The considered machine learning algorithms were logistic regression, support vector machine, Bayes point machine, boosted decision tree, decision forest, and decision jungle. These algorithms were mainly evaluated in terms of the areas under the receiver-operating characteristic (ROC) curve (AUC) and accuracy values. The performance of the algorithm that produced the best result was compared with a nomogram to predict overall survival in tongue cancer patients.

Results: The boosted decision-tree algorithm outperformed other algorithms. When compared with a nomogram using external validation data, the boosted decision tree produced an accuracy of 88.7% while the nomogram showed an accuracy of 60.4%. In addition, it was found that age of patient, T stage, radiotherapy, and the surgical resection were the most prominent features with significant influence on the machine learning model's performance to predict overall survival.

Conclusion: The machine learning model provides more personalized and reliable prognostic information of tongue cancer than the nomogram. However, the level of transparency offered by the nomogram in estimating patients' outcomes seems more confident and strengthened the principle of shared decision making between the patient and clinician. Therefore, a combination of a nomogram - machine learning (NomoML) predictive model may help to improve care, provides information to patients, and facilitates the clinicians in making tongue cancer management-related decisions.
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http://dx.doi.org/10.1016/j.ijmedinf.2020.104313DOI Listing
January 2021

The budding and depth of invasion model in oral cancer: A systematic review and meta-analysis.

Oral Dis 2020 Oct 8. Epub 2020 Oct 8.

Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.

Background: Tumour budding (B) and depth of invasion (D) have both been reported as promising prognostic markers in oral squamous cell carcinoma (OSCC). This meta-analysis assessed the prognostic value of the tumour budding and depth of invasion combination (BD model) in OSCC.

Methods: Databases including Ovid MEDLINE, PubMed, Scopus and Web of Science were searched for articles that studied the BD model as a prognosticator in OSCC. PICO search strategy was "In OSCC patients, does BD model have a prognostic power?" We used the reporting recommendations for tumour marker prognostic studies (REMARK) criteria to evaluate the quality of studies eligible for systematic review and meta-analysis.

Results: Nine studies were relevant as they analysed the BD model for prognostication of OSCC. These studies used either haematoxylin and eosin (HE) or pan-cytokeratin (PCK)-stained resected sections of OSCC. Our meta-analysis showed a significant association of BD model with OSCC disease-free survival (hazard ratio = 2.02; 95% confidence interval = 1.44-2.85).

Conclusions: The BD model is a simple and reliable prognostic indicator for OSCC. Evaluation of the BD model from HE- or PCK-stained sections could facilitate individualized treatment planning for OSCC patients.
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http://dx.doi.org/10.1111/odi.13671DOI Listing
October 2020

Stromal categorization in early oral tongue cancer.

Virchows Arch 2021 May 21;478(5):925-932. Epub 2020 Sep 21.

Institute of Biomedicine, Pathology, University of Turku and Turku University Hospital, Turku, Finland.

Stromal categorization has been used to classify many epithelial cancer types. We assessed the desmoplastic reaction and compared its significance with other stromal characteristics in early (cT1-2N0) oral tongue squamous cell carcinoma (OTSCC). In this multi-institutional study, we included 308 cases treated for early OTSCC at five Finnish university hospitals or at the A.C. Camargo Cancer Center in São Paulo, Brazil. The desmoplastic reaction was classified as immature, intermediate, or mature based on the amount of hyalinized keloid-like collagen and myxoid stroma. We compared the prognostic value of the desmoplastic reaction with a stromal grading system based on tumor-stroma ratio and stromal tumor-infiltrating lymphocytes. We found that a high amount of stroma with a weak infiltration of lymphocytes was associated statistically significantly with a worse disease-free survival with a hazard ratio (HR) of 2.68 (95% CI 1.26-5.69), worse overall survival (HR 2.95, 95% CI 1.69-5.15), and poor disease-specific survival (HR 2.66, 95% CI 1.11-6.33). Tumors having a high amount of stroma with a weak infiltration of lymphocytes were also significantly associated with a high rate of local recurrence (HR 4.13, 95% CI 1.67-10.24), but no significant association was found with lymph node metastasis (HR 1.27, 95% CI 0.37-4.35). Categorization of the stroma based on desmoplastic reaction (immature, intermediate, mature) showed a low prognostic value for early OTSCC in all survival analyses (P > 0.05). In conclusion, categorization of the stroma based on the amount of stroma and its infiltrating lymphocytes shows clinical relevance in early OTSCC superior to categorization based on the maturity of stroma.
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http://dx.doi.org/10.1007/s00428-020-02930-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099799PMC
May 2021

Cell-in-cell phenomenon associates with aggressive characteristics and cancer-related mortality in early oral tongue cancer.

BMC Cancer 2020 Sep 3;20(1):843. Epub 2020 Sep 3.

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.

Background: Cell-in-cell structures (caused by cell cannibalistic activity) have been related to prognosis of many cancers. This is the first multi-institutional study to assess the prognostic impact of cell-in-cell structures in a large cohort of early oral tongue squamous cell carcinomas (OTSCC).

Methods: A total of 308 cases from five Finnish University Hospitals and from the A.C. Camargo Cancer Center, São Paulo, Brazil, were included in this study. Cell-in-cell structures were evaluated on surgical postoperative sections that stained with hematoxylin and eosin staining.

Results: We found that cell-in-cell structures associated with cancer-related mortality in univariable analysis with a hazard ratio (HR) of 2.99 (95%CI 1.52-5.88; P = 0.001). This association was confirmed in multivariable analysis (HR 2.22, 95%CI 1.12-4.44; P = 0.024). In addition, statistically significant associations were observed between the cell-in-cell structures and other adverse histopathologic characteristics including deep invasion (P <  0.001), high index of tumor budding (P = 0.007), worst pattern of invasion (P <  0.001), perineural invasion (P = 0.01), and stroma-rich pattern (P = 0.001).

Conclusions: Our findings demonstrate a significant relationship between cell-in-cell formation and aggressive characteristics of early OTSCC. Cell-in-cell structures have a distinct impact as a novel prognostic indicator in early OTSCC and they can be easily assessed during routine pathology practice.
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http://dx.doi.org/10.1186/s12885-020-07342-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469910PMC
September 2020

Characteristics of Laryngeal Osteosarcoma: A Critical Review.

Oncol Ther 2020 Jun 11;8(1):33-44. Epub 2020 Feb 11.

Coordinator of the International Head and Neck Scientific Group, Padua, Italy.

Laryngeal sarcomas constitute an extremely rare entity among head and neck malignancies. Furthermore, most of them are chondrosarcomas, and the osteogenic form remains a true rarity. In general, there is a lack of information on the characteristics of laryngeal osteosarcoma. Thus, we sought to critically review the existing world literature on laryngeal osteosarcoma in order to develop a more accurate clinicopathological profile of this malignancy. Laryngeal osteosarcoma has a predilection for elderly male patients, as 87% were male in the present series and the mean age was 62 years (range 32-80), and without a direct association with tobacco exposure. Osteosarcoma of the larynx is typically a highly malignant neoplasm that metastasizes early, has a propensity for hematogenous spread and also has a marked tendency to recur. Twelve (41%) out of the 29 cases in the present review with follow-up data had metastatic disease. The aspects that distinguish osteosarcoma from its differential diagnostic alternatives are discussed in this review.
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http://dx.doi.org/10.1007/s40487-020-00110-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359981PMC
June 2020

Addition of the tumour-stroma ratio to the 8th edition American Joint Committee on Cancer staging system improves survival prediction for patients with oral tongue squamous cell carcinoma.

Histopathology 2020 Nov 12;77(5):810-822. Epub 2020 Sep 12.

Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy.

Aims: One of the objectives of current research is to customise the treatment of cancer patients. The achievement of this objective requires stratification of patients based on the most significant prognostic factors. The aims of this study were to evaluate the prognostic value of the tumour-stroma ratio (TSR), defined as the proportion of tumour cells relative to surrounding stroma, in patients with oral tongue squamous cell carcinoma (OTSCC), and to develop a prognostic nomogram based on the most significant clinicopathological features.

Methods And Results: Clinicopathological data of 211 patients treated at 'Ospedali Riuniti' General Hospital (Ancona, Italy) for OTSCC were collected. One hundred and thirty-nine patients were restaged according to the 8th edition American Joint Committee on Cancer (AJCC) staging system. Evaluation of the TSR was performed on haematoxylin and eosin-stained slides, and correlation with survival outcomes was evaluated. In addition, with the aim of integrating the independent value of the TSR with the 8th edition AJCC staging system, a prognostic nomogram for OTSCC has been developed. OTSCC with a low TSR (i.e. a high proportion of stroma and a low proportion of tumour cells) was shown to have negative prognostic value in terms of disease-specific survival, with a hazard ratio (HR) of 1.883 and a 95% confidence interval (CI) of 1.033-3.432 (P = 0.039), and overall survival (HR = 1.747, 95% CI 0.967-3.154; P = 0.044), independently of other histological and clinical parameters. For the cohort of 139 patients restaged according to the 8th edition AJCC staging system, variables correlating with a poor prognosis were: the TSR, perineural invasion, and sex. The nomogram built on these parameters showed good predictive capacity, outperforming the 8th edition AJCC staging system in stratifying disease-specific survival in OTSCC patients.

Conclusions: Including the TSR in the predictive model could improve risk stratification of OTSCC patients and aid in making treatment decisions.
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http://dx.doi.org/10.1111/his.14202DOI Listing
November 2020

High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study.

Neoplasia 2020 09 22;22(9):333-342. Epub 2020 Jun 22.

Institute of Biomedicine, University of Turku and Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland.

Objectives: Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines.

Materials And Methods: 176 surgically resected stage I-IV lung adenocarcinomas were histologically reclassified according to WHO 2015 guidelines. A modified classification subdividing the acinar subtype into classic acinar, complex glandular and cribriform subtypes was further applied and potentially prognostic histopathological characteristics such as tumor-infiltrating lymphocytes were evaluated. 148 patients with stage I-III tumors and complete follow-up data were included in the survival analyses. TMB was determined by a commercial next generation sequencing panel from 131 tumors, out of which 105 had survival data available.

Results: Predominant micropapillary, solid and complex glandular as well as nonpredominant cribriform histological subtypes were associated with significantly shorter survival. High TMB concentrated in micropapillary, solid and acinar predominant subtypes. Interestingly, TMB ≥ 14 mutations/MB conferred a stage- and histology-independent survival benefit compared to TMB < 14 in multivariable analysis for overall (HR 0.284, 95% CI 0.14-0.59, P=0.001) and disease-specific survival (HR 0.213, 95% CI 0.08-0.56, P=0.002).

Conclusion: TMB was an independent biomarker of favorable prognosis in our cohort of lung adenocarcinoma despite being associated with predominant histological subtypes considered aggressive.
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http://dx.doi.org/10.1016/j.neo.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317687PMC
September 2020

Nonmalignant Formalin-Fixed Paraffin-Embedded Tissues as a Source to Study Germline Variants and Cancer Predisposition: A Systematic Review.

Biopreserv Biobank 2020 Aug 16;18(4):337-345. Epub 2020 Jun 16.

Department of Pathology, University of Helsinki, Helsinki, Finland.

Archived formalin-fixed paraffin-embedded (FFPE) specimens from nonmalignant tissues derived from cancer patients are a vast and potentially valuable resource for high-quality genotyping analyses and could have a role in establishing inherited cancer risk. We systematically searched PubMed, Ovid MEDLINE, and Scopus databases for all articles that compared genotyping performance of DNA from nonmalignant FFPE tissue with blood DNA derived from cancer patients irrespective of tumor type. Two independent researchers screened the retrieved studies, removed duplicates, excluded irrelevant studies, and extracted genotyping data from the eligible studies. These studies included, but were not limited to, genotyping technique, reported call rate, and concordance. Thirteen studies were reviewed, in which DNA from nonmalignant FFPE tissues derived from cancer patients was successfully purified and genotyped. All these studies used different approaches for genotyping of DNA from nonmalignant FFPE tissues to amplify single nucleotide polymorphisms (SNPs) and to estimate of loss of heterozygosity. The concordance between genotypes from nonmalignant FFPE tissues and blood derived from cancer patients was observed to be high, whereas the call rate of the tested SNPs was not reported in all included studies. This review illustrates that DNA from nonmalignant FFPE tissues derived from cancer patients can serve as an alternative and reliable source for assessment of germline DNA for various purposes, including assessment of cancer predisposition.
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http://dx.doi.org/10.1089/bio.2020.0021DOI Listing
August 2020

Risk stratification in oral squamous cell carcinoma using staging of the eighth American Joint Committee on Cancer: Systematic review and meta-analysis.

Head Neck 2020 10 17;42(10):3002-3017. Epub 2020 Jun 17.

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.

The eighth edition of the American Joint Committee on Cancer (AJCC8) staging manual has major changes in oral squamous cell carcinoma (OSCC). We searched PubMed, OvidMedline, Scopus, and Web of Science for studies that examined the performance of AJCC8 in OSCC. A total of 40 808 patients were included in the studies of our meta-analysis. A hazard ratio (HR) of 1.87 (95%CI 1.78-1.96) was seen for stage II, 2.65 (95%CI 2.51-2.80) for stage III, 3.46 (95%CI 3.31-3.61) for stage IVa, and 7.09 (95%CI 4.85-10.36) for stage IVb. A similar gradual increase in risk was noted for the N classification. For the T classification, however, there was a less clear variation in risk between T3 and T4. AJCC8 provides a good risk stratification for OSCC. Future research should examine the proposals introduced in the published studies to further improve the performance of AJCC8.
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http://dx.doi.org/10.1002/hed.26344DOI Listing
October 2020

Staging and grading of oral squamous cell carcinoma: An update.

Oral Oncol 2020 08 20;107:104799. Epub 2020 May 20.

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland. Electronic address:

Oral squamous cell carcinoma (OSCC) is a common malignancy of the head and neck region. OSCC has a relatively low survival rate and the incidence of the disease is increasing in some geographic areas. Staging and grading of OSCC are established prerequisites for management, as they influence risk stratification and are the first step toward personalized treatment. The current AJCC/UICC TNM staging (8th edition, 2017) of OSCC has included significant modifications through the incorporation of depth of invasion in the T stage and extracapsular spread/extranodal extension in the N stage. Further modifications for AJCC 8 have been suggested. On the other hand, the World Health Organization (WHO) classification (4th edition, 2017) still endorses a simple, differentiation-based histopathologic grading system of OSCC (despite its low prognostic value) and ignores factors such as tumor growth pattern and dissociation, stromal reactions (desmoplasia, local immune response), and tumor-stroma ratio. The various controversies and possible developments of the current staging and grading criteria of OSCC are briefly discussed in this update together with possible applications of artificial intelligence in the context of screening and risk stratification.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104799DOI Listing
August 2020

A systematic review of predictive models for recurrence and mortality in patients with tongue cancer.

Eur J Cancer Care (Engl) 2020 03;29(2):e13211

Department of Pathology, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1111/ecc.13211DOI Listing
March 2020

Overall assessment of tumor-infiltrating lymphocytes in head and neck squamous cell carcinoma: time to take notice.

Acta Otolaryngol 2020 Mar 5;140(3):246-248. Epub 2020 Feb 5.

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

The immune response has an important role in cancer progression. At the same time, anti-tumor effect of the immune response has been speculated to cause destruction of cancer cells. Recent studies have highlighted the significance of tumor-infiltrating lymphocytes (TILs) in different cancers. The International Immuno-Oncology Biomarkers Working Group has in 2017 published a practical review proposing a standardized method to assess TILs in the routine hematoxylin and eosin (HE) stained sections. To discuss the association between TILs and survival in head and neck squamous cell carcinoma (HNSCC). We review recent studies having assessed TILs in HNSCC and showing that tumors having low TILs associate significantly with worse survival. These findings underline that HNSCC cases with low TILs might benefit from multimodality treatment and might be indicated to receive immunotherapy. The evaluation of TILs using routine HE-stained sections is practical and can be considered in assessment of antitumor activity. Here, we highlight the impact of overall assessment of TILs using the routine HE-stained specimens in HNSCC.
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http://dx.doi.org/10.1080/00016489.2020.1720284DOI Listing
March 2020

Histological characteristics of early-stage oral tongue cancer in young versus older patients: A multicenter matched-pair analysis.

Oral Dis 2020 Jul 14;26(5):1081-1085. Epub 2020 Feb 14.

Department of Pathology, University of Helsinki, Helsinki, Finland.

Little is known about the histopathological characteristics that may differentiate early oral tongue cancer (OTSCC) between young and older patients. From a total of 311 cases diagnosed with clinically early-stage OTSCC at 6 institutions, only 42 patients were young patients were aged ≤45 years. For comparison, 42 patients >60 years old were matched for center of management, clinical stage and gender. We compared epithelial and stromal histopathologic parameters between the two groups. Most of the parameters were similar between the two groups, although the young patients appeared to have marginally higher intensity of tumor budding, histologic risk score, infiltrative pattern of invasion and tumor-stroma ratio. However, none of the factors showed significant difference when comparing the two groups. The histological parameters reflect mechanisms of invasive growth and tissue response to invasive growth, but not the etiological difference in OTSCC between young and older patients. Further investigations are necessary to compare the genetic background of early OTSCC in the two groups.
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http://dx.doi.org/10.1111/odi.13288DOI Listing
July 2020

Prognostication for oral squamous cell carcinoma patients based on the tumour-stroma ratio and tumour budding.

Histopathology 2020 May 3;76(6):906-918. Epub 2020 May 3.

Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil.

Aims: Previous studies have demonstrated that the tumour-stroma ratio (TSR) and tumour budding are of prognostic value for oral squamous cell carcinomas (OSCCs). The aim of this study was to evaluate the prognostic significance of those histological parameters, individually and in combination, for OSCC.

Methods And Results: The TSR and tumour budding (the presence of five or more buds at the invasive front) were estimated in 254 patients with OSCC. The clinicopathological association was investigated with a chi-square test, and the prognostic significance (cancer-specific survival and disease-free survival) was verified with Kaplan-Meier analysis and the Cox proportional hazard model. The TSR (≥50%, stroma-rich) was significantly and independently associated with both shortened cancer-specific survival and poor disease-free survival, whereas tumour budding was significantly associated with reduced cancer-specific survival. The TSR/tumour budding model was independently associated with a high risk of cancer mortality and recurrence (disease-free survival). In patients with early-stage tumours (clinical stage I and II, n = 103), the TSR, tumour budding and the TSR/tumour budding model were significantly associated with both cancer-related death and recurrence, whereas, in advanced-stage tumours (clinical stage III and IV, n = 144), only the TSR and the TSR/tumour budding model were significantly associated with cancer-specific survival.

Conclusions: The TSR, tumour budding and their combination provide significant information on OSCC outcome, suggesting that their incorporation in the routine evaluation of histopathological specimens might be useful in prognostication for OSCC patients.
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http://dx.doi.org/10.1111/his.14070DOI Listing
May 2020

Comparison of supervised machine learning classification techniques in prediction of locoregional recurrences in early oral tongue cancer.

Int J Med Inform 2020 04 28;136:104068. Epub 2019 Dec 28.

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.

Background: The proper estimate of the risk of recurrences in early-stage oral tongue squamous cell carcinoma (OTSCC) is mandatory for individual treatment-decision making. However, this remains a challenge even for experienced multidisciplinary centers.

Objectives: We compared the performance of four machine learning (ML) algorithms for predicting the risk of locoregional recurrences in patients with OTSCC. These algorithms were Support Vector Machine (SVM), Naive Bayes (NB), Boosted Decision Tree (BDT), and Decision Forest (DF).

Materials And Methods: The study cohort comprised 311 cases from the five University Hospitals in Finland and A.C. Camargo Cancer Center, São Paulo, Brazil. For comparison of the algorithms, we used the harmonic mean of precision and recall called F1 score, specificity, and accuracy values. These algorithms and their corresponding permutation feature importance (PFI) with the input parameters were externally tested on 59 new cases. Furthermore, we compared the performance of the algorithm that showed the highest prediction accuracy with the prognostic significance of depth of invasion (DOI).

Results: The results showed that the average specificity of all the algorithms was 71% . The SVM showed an accuracy of 68% and F1 score of 0.63, NB an accuracy of 70% and F1 score of 0.64, BDT an accuracy of 81% and F1 score of 0.78, and DF an accuracy of 78% and F1 score of 0.70. Additionally, these algorithms outperformed the DOI-based approach, which gave an accuracy of 63%. With PFI-analysis, there was no significant difference in the overall accuracies of three of the algorithms; PFI-BDT accuracy increased to 83.1%, PFI-DF increased to 80%, PFI-SVM decreased to 64.4%, while PFI-NB accuracy increased significantly to 81.4%.

Conclusions: Our findings show that the best classification accuracy was achieved with the boosted decision tree algorithm. Additionally, these algorithms outperformed the DOI-based approach. Furthermore, with few parameters identified in the PFI analysis, ML technique still showed the ability to predict locoregional recurrence. The application of boosted decision tree machine learning algorithm can stratify OTSCC patients and thus aid in their individual treatment planning.
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http://dx.doi.org/10.1016/j.ijmedinf.2019.104068DOI Listing
April 2020

Exhaled breath analysis in the diagnosis of head and neck cancer.

Head Neck 2020 04 19;42(4):787-793. Epub 2019 Dec 19.

International Head and Neck Scientific Group, Padua, Italy.

Head and neck cancer (HNC) comprises a heterogeneous group of upper aerodigestive tract malignant neoplasms, the most frequent of which is squamous cell carcinoma. HNC forms the eighth most common cancer type and the incidence is increasing. However, survival has improved only moderately during the past decades. Currently, early diagnosis remains the mainstay for improving treatment outcomes in this patient population. Unfortunately, screening methods to allow early detection of HNC are not yet established. Therefore, many cases are still diagnosed at advanced stage, compromising outcomes. Exhaled breath analysis (EBA) is a diagnostic tool that has been recently introduced for many cancers. Breath analysis is non-invasive, cost-effective, time-saving, and can potentially be applied for cancer screening. Here, we provide a summary of the accumulated evidence on the feasibility of EBA in the diagnosis of HNC.
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http://dx.doi.org/10.1002/hed.26043DOI Listing
April 2020

Machine learning application for prediction of locoregional recurrences in early oral tongue cancer: a Web-based prognostic tool.

Virchows Arch 2019 Oct 17;475(4):489-497. Epub 2019 Aug 17.

Research Programme in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Estimation of risk of recurrence in early-stage oral tongue squamous cell carcinoma (OTSCC) remains a challenge in the field of head and neck oncology. We examined the use of artificial neural networks (ANNs) to predict recurrences in early-stage OTSCC. A Web-based tool available for public use was also developed. A feedforward neural network was trained for prediction of locoregional recurrences in early OTSCC. The trained network was used to evaluate several prognostic parameters (age, gender, T stage, WHO histologic grade, depth of invasion, tumor budding, worst pattern of invasion, perineural invasion, and lymphocytic host response). Our neural network model identified tumor budding and depth of invasion as the most important prognosticators to predict locoregional recurrence. The accuracy of the neural network was 92.7%, which was higher than that of the logistic regression model (86.5%). Our online tool provided 88.2% accuracy, 71.2% sensitivity, and 98.9% specificity. In conclusion, ANN seems to offer a unique decision-making support predicting recurrences and thus adding value for the management of early OTSCC. To the best of our knowledge, this is the first study that applied ANN for prediction of recurrence in early OTSCC and provided a Web-based tool.
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http://dx.doi.org/10.1007/s00428-019-02642-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828835PMC
October 2019

Hallmarks of cancer: Tumor budding as a sign of invasion and metastasis in head and neck cancer.

Head Neck 2019 10 22;41(10):3712-3718. Epub 2019 Jul 22.

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.

Invasion and metastasis are hallmarks of cancer. The concept of tumor budding at tumor-host interface has been documented in many carcinomas. A growing body of evidence indicates that tumor budding is a sign of invasion and early step for metastasis of many epithelial cancers including head and neck squamous cell carcinoma (HNSCC). In addition, recent research has underlined the importance of tumor budding as a promising prognosticator in HNSCC. This review summarizes the findings regarding tumor budding in HNSCC and focuses on the role of tumor budding in invasion and metastasis. Also, we highlight the prognostic significance of tumor budding in HNSCC and its potential for improving clinical decision making in terms of recommending optimal individualized treatment for this patient population.
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http://dx.doi.org/10.1002/hed.25872DOI Listing
October 2019

Assessment of Tumor-infiltrating Lymphocytes Predicts the Behavior of Early-stage Oral Tongue Cancer.

Am J Surg Pathol 2019 10;43(10):1392-1396

Departments of Pathology.

Tumor-infiltrating lymphocytes (TILs) have shown a promising prognostic value in many epithelial cancers. We sought to assess the prognostic value of TILs in a multicenter cohort of early oral tongue squamous cell carcinoma (OTSCC). The percentage of TILs was assessed on the surgical resection slides stained with hematoxylin and eosin. The assessment of TILs was performed in the stromal compartment and in the intraepithelial compartment (at the invasive front and at the center of the tumor). We followed the method that was described recently by the International Immuno-Oncology Biomarker Working Group for the assessment of TILs. A total of 308 cases from the 5 Finnish university hospitals and from A.C. Camargo Cancer Center, São Paulo, Brazil, were included. We found a promising prognostic value for stromal TILs at the invasive front in the multivariable analysis with a hazard ratio of 2.61 (95% confidence interval [CI], 1.77-3.83; P<0.001) for overall survival, 1.99 (95% CI, 1.07-3.69; P=0.040) for disease-specific survival, and 1.94 (95% CI, 1.14-3.29; P=0.020) for disease-free survival. In conclusion, evaluation of TILs is simple and can aid in identifying the high-risk cases of early OTSCC. The method introduced by the International Immuno-Oncology Biomarker Working Group can be used for standardized determination of TILs in early OTSCC.
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http://dx.doi.org/10.1097/PAS.0000000000001323DOI Listing
October 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

A Proposal to Revise the Histopathologic Grading System of Early Oral Tongue Cancer Incorporating Tumor Budding.

Am J Surg Pathol 2019 05;43(5):703-709

Pathology.

The World Health Organization (WHO) grading system has a low prognostic value for early-stage oral tongue squamous cell carcinoma; greater prognostic power has been shown with tumor budding analysis. In this study, we combined tumor budding analysis with histopathologic grading according to WHO 2017. In our proposal, a revised grade I tumor is defined as a "well differentiated cohesive tumor"; revised grade II as a "moderately differentiated and/or slightly dissociated tumor"; and revised grade III as a "poorly differentiated and/or dissociated tumor." We evaluated the prognostic value of this proposed grading system in a multicenter cohort of 311 cases of early oral tongue squamous cell carcinoma. The proposed grading system showed significant prognostic value in multivariable analysis for disease-specific survival with a hazard ratio of 3.86 and a 95% confidence interval of 1.36-10.9 (P=0.001). For disease-free survival, the proposed grading system showed good predictive power in multivariable analysis (hazard ratio, 2.07; 95% confidence interval, 1.00-4.27; P=0.009). The conventional WHO grading system showed a low prognostic value for disease-specific survival and disease-free survival (P>0.05). In conclusion, the prognostic power of the WHO histopathologic grading improved significantly with incorporation of tumor budding. Our proposed grading system can be easily included in pathology reports.
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http://dx.doi.org/10.1097/PAS.0000000000001241DOI Listing
May 2019

The 8th Edition of the American Joint Committee on Cancer (AJCC8) Staging Manual: any improvement in the prognostication of oral tongue cancer?

Chin Clin Oncol 2019 Oct 8;8(S1):S8. Epub 2019 Jan 8.

Department of Pathology, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland; Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

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http://dx.doi.org/10.21037/cco.2018.12.04DOI Listing
October 2019

Does evaluation of tumour budding in diagnostic biopsies have a clinical relevance? A systematic review.

Histopathology 2019 Mar 28;74(4):536-544. Epub 2019 Jan 28.

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

Tumour budding has emerged as a promising prognostic marker in many cancers. We systematically reviewed all studies that evaluated tumour budding in diagnostic biopsies. We conducted a systematic review of PubMed, MEDLINE, Scopus, Web of Science and Cochrane library for all articles that have assessed tumour budding in diagnostic (i.e. pretreatment or pre-operative) biopsies of any tumour type. Two independent researchers screened the retrieved studies, removed duplicates, excluded irrelevant studies and extracted data from the eligible studies. A total of 13 reports comprising 11 cohorts were found to have studied tumour budding in diagnostic biopsies. All these reports showed that evaluation of tumour budding in diagnostic biopsies was easily applicable. A strong association was observed between tumour budding score in diagnostic biopsies and corresponding surgical samples. Evaluation of tumour budding in diagnostic biopsies had a significant prognostic value for lymph node metastasis and patient survival. In all studies, tumour budding was a valuable marker of tumour aggressiveness and can be evaluated in technically satisfactory diagnostic biopsies. Thus, the assessment of tumour budding seems to identify the behaviour of cancer, and therefore to facilitate treatment planning.
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http://dx.doi.org/10.1111/his.13793DOI Listing
March 2019

The prognostic value of immune checkpoints in oral squamous cell carcinoma.

Oral Dis 2019 Sep 12;25(6):1435-1445. Epub 2018 Nov 12.

Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, Helsinki, Finland.

Background: Despite the importance of immune checkpoints in immunotherapy, the prognostic value of these molecules remains controversial in oral squamous cell carcinoma (OSCC). We performed a systematic review to investigate the prognostic significance of the immune checkpoints in OSCC.

Materials: A systematic search was conducted in Ovid Medline, Scopus and Cochrane libraries, and all studies that evaluated the prognostic significance of immune checkpoints in OSCC were systematically retrieved.

Results: Twelve immune checkpoints/modulators were studied for their prognostic values in OSCC patients between 1985 and 2017. Seven immune checkpoints (FKBP51, B7-H4, B7-H6, ALHD1, PD-L1, B7-H3 and IDO1) were reported to be associated with poor patients' survival in at least one study, and five (CTLA-4, TLT-2, VISTA, PD-L2 and PD-1) did not have a significant prognostic value. PD-L1 results were controversial as it was reported to be associated with both better and worse patients' survival.

Conclusions: Even though immune checkpoint markers had high expectation for OSCC prognostication, our systematic review revealed that the majority of them had been studied only once. The other molecules, which had been studied more than once, had controversial findings, except B7-H3.
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http://dx.doi.org/10.1111/odi.12991DOI Listing
September 2019

Expression of Plasma miRNA-221 in Colorectal Carcinoma Patients and its Diagnostic Significance in Comparison with p53 Expression.

Clin Lab 2018 Sep;64(9):1527-1533

Background: Colorectal carcinoma development progresses through a sequence of normal mucosa-polyp-carcinoma. Early detection of premalignancy is crucial for improved outcomes. We evaluated the diagnostic performance of plasma miRNA-221 and its feasibility in discriminating premalignant from malignant neoplasms and correlating it with immunohistochemical p53 expression.

Methods: A total of 109 plasma samples were collected (76 carcinoma, 14 premalignant, and 19 controls). MiRNA221 was quantified by qPCR for calculation of ∆Ct using RNU6B as endogenous control. p53 immunohistochemical staining was performed on corresponding tissue.

Results: Plasma miRNA-221 and p53 in tissues were significantly overexpressed in the malignant group when compared with the premalignant and control groups. Plasma miRNA-221 was increased in late-stage tumors with nodal or distant metastasis. ROC curve construction for distinguishing between malignant and premalignant tumors revealed a cutoff value of 2.97 with 74% sensitivity, 79% specificity, 73.7% positive predictive value and 78.6% negative predictive value (AUC = 0.824; p = 0.001). Plasma miRNA-221 significantly correlated with p53 in cancer samples (r = 0.507).

Conclusions: MiRNA-221 could have a diagnostic role in differentiating malignant from premalignant neoplasms and could also serve as a predictive marker indicating tumor progression.
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http://dx.doi.org/10.7754/Clin.Lab.2018.180408DOI Listing
September 2018

Small oral tongue cancers (≤ 4 cm in diameter) with clinically negative neck: from the 7th to the 8th edition of the American Joint Committee on Cancer.

Virchows Arch 2018 Oct 23;473(4):481-487. Epub 2018 Jul 23.

Department of Pathology, University of Turku, Turku, Finland.

One of the main changes in the 8th edition of the American Joint Committee on Cancer (AJCC) for staging of oral cancer is the inclusion of depth of invasion (DOI) in the T category. However, cancers in different oral subsites have variable behavior, with oral tongue squamous cell carcinoma (OTSCC) being the most aggressive one even at early stage. Thus, it is necessary to evaluate the performance of this new T category in homogenous cohort of early OTSCC. Therefore, we analyzed a large cohort of patients with a small (≤ 4 cm) OTSCC to demonstrate the differences in T stage between the AJCC 7th and 8th editions. A total of 311 early-stage cases (AJCC 7th) of OTSCC were analyzed. We used 5 mm and 10 mm DOI for upstaging from T1 to T2 and from T2 to T3 respectively, as in the AJCC 8th. We further reclassified the cases according to our own proposal suggesting 2 mm to upstage to T2 and 4 mm to upstage to T3. According to AJCC 7th, there were no significant differences in the survival analysis. When we applied the 8th edition, many cases were upstaged to T3 and thus associated with worse disease-specific survival (HR 2.37, 95% CI 1.12-4.99) and disease-free survival (HR 2.12, 95% CI 1.09-4.08). Based on our proposal, T3 cases were associated with even worse disease-specific survival (HR 4.19, 95% CI 2.27-7.74). The 8th edition provides better survival prediction for OTSCC than the 7th and can be further optimized by lowering the DOI cutoffs.
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http://dx.doi.org/10.1007/s00428-018-2417-yDOI Listing
October 2018