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Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 34782

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Dr. Sven Otto

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Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, University Hospital, LMU, München, Germany
Interests: OMFS; drug therapy; 3D bioprinting; bone regeneration; tissue engineering
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The main goal of this Special Issue of the journal Cancer is to find answers for a better understanding of oral squamous cell carcinoma (OSCC) and to point out modern therapies that are state-of-the-art.
The biological and immunological aspects of OSCC are of particular interest, especially for estimating the prognosis of this type of cancer, as well as specific clinical data related to the use of prognostic and therapeutic markers. Moreover, studies aimed at understanding important complications in the therapy of OSCC (e.g., the mechanism of metastasis and epithelial–mesenchymal transition (EMT)), the failure of specific therapies (e.g., of immunotherapy or chemotherapy due to the mutation burden), as well as that of transplants (e.g., flaps or dental implants after OSCC therapy) are welcome.
Metabolic, immunological, and other specific features of OSCC (e.g., stem cell markers, hypoxic status) are also of interest.
Therefore, we welcome manuscripts describing biological, immunological, and physiological markers of OSCC and the translation of these data into modern techniques for routine clinical practice for more specific and individual therapeutic options for this disease.

Prof. Sven Otto
Guest Editor

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Keywords

Prognosis
metastasis
immune escape
metabolism
mutation
hypoxia

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Published Papers (10 papers)

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10 pages, 394 KiB

Open AccessArticle

Postoperative Delirium in Patients with Oral Cancer: Is Intraoperative Fluid Administration a Neglected Risk Factor?

by Katharina Theresa Obermeier, Moritz Kraus, Wenko Smolka, Jochen Henkel, Thomas Saller, Sven Otto and Paris Liokatis

Cancers 2022, 14(13), 3176; https://doi.org/10.3390/cancers14133176 - 28 Jun 2022

Cited by 10 | Viewed by 2018

Abstract

Squamous cell carcinoma (SCC) is a malignant tumor derived from squamous cells and can be found in different localizations. In the oral cavity especially, it represents the most common type of malignant tumor. First-line therapy for oral squamous cell carcinoma (OSCC) is surgery, including tumor resection, neck dissection, and maybe reconstruction. Although perioperative mortality is low, complications such as delirium are very common, and may have long-lasting consequences on the patient’s quality of life. This study examines if excessive fluid administration, among other parameters, is an aggravating factor for the development of postoperative delirium. A total of 198 patients were divided into groups concerning the reconstruction technique used: group A for primary wound closure or reconstruction with a local flap, and group B for microsurgical reconstruction. The patients with and without delirium in both groups were compared regarding intraoperative fluid administration, fluid balance, and other parameters, such as blood loss, duration of surgery and overall ventilation, alcohol consumption, and creatinine, albumin, natrium, and hematocrit levels. The logistic regression for group A shows that fluid intake (p = 0.02, OR = 5.27, 95% CI 1.27–21.8) and albumin levels (p = 0.036, OR = 0.22, CI 0.054–0.908) are independent predictors for the development of delirium. For group B, gender (p = 0.026, OR = 0.34, CI 0.133–0.879) with a protective effect for females, fluid intake (p = 0.003, OR = 3.975, CI 1.606–9.839), and duration of ventilation (p = 0.025, OR = 1.178, CI 1.021–1.359) are also independent predictors for delirium. An intake of more than 3000 mL for group A, and 4150 mL for group B, increases the risk of delirium by approximately five and four times, respectively. Fluid management should be considered carefully in patients with OSCC, in order to reduce the occurrence of postoperative delirium. Different factors may become significant for the development of delirium regarding different surgical procedures. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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15 pages, 1213 KiB

Open AccessArticle

Effects of Red Blood Cell Transfusions on Distant Metastases of Oral Squamous Cell Carcinomas

by Leonard Simon Brandenburg, Marc Christian Metzger, Philipp Poxleitner, Pit Jacob Voss, Kirstin Vach, Johannes Hell, Konstantin Hasel, Julia Vera Weingart, Steffen Jochen Schwarz and Michael Andreas Ermer

Cancers 2022, 14(1), 138; https://doi.org/10.3390/cancers14010138 - 28 Dec 2021

Cited by 2 | Viewed by 2321

Abstract

There is no consensus on the effect of red blood cell (RBC) transfusions on patients with oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the association between RBC administration and the occurrence of distant metastases (M+) after surgical treatment of OSCC. All medical records of patients who underwent primary surgery for OSCC in our department (2003–2019) were analyzed retrospectively (n = 609). Chi and Cox regression models were used to analyze the influence of transfusion on the development of M+, and survival rates. Kaplan–Meier curves were used for graphical presentation. A multitude of patient-specific factors showed a statistical impact in univariate analysis (transfusion, age, gender, diabetes, pT, pN, L, V, Pn, G, UICC, adjuvant therapy, free microvascular transplant, preoperative hemoglobin level). Transfusion status and pN stage were the only variables that showed a significant correlation to M+ in the multivariate Cox model. The hazard ratios for the occurrence of M+ were 2.42 for RBC transfusions and 2.99 for pN+. Administration of RBC transfusions was identified as a significant prognostic parameter for the occurrence of distant metastases after surgical treatment of OSCC. Hence, the administration of RBC transfusions should be considered carefully in the perioperative management. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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14 pages, 1682 KiB

Open AccessArticle

Tonsillar Cancer with High CD8⁺ T-Cell Infiltration Features Increased Levels of Dendritic Cells and Transcriptional Regulation Associated with an Inflamed Tumor Microenvironment

by David Gomez Jimenez, Aastha Sobti, David Askmyr, Christina Sakellariou, Sofia Carreira Santos, Sabine Swoboda, Ola Forslund, Lennart Greiff and Malin Lindstedt

Cancers 2021, 13(21), 5341; https://doi.org/10.3390/cancers13215341 - 25 Oct 2021

Cited by 8 | Viewed by 2150

Abstract

Human papillomavirus (HPV) is the main causal agent of tonsillar cancer (TC) and HPV⁺ TC has a favorable prognosis compared to HPV⁻ disease. In this study, we examined aspects of the tumor microenvironment of TC, focusing on T-cells, dendritic cells (DC), and macrophages. Fresh biopsies of TC and the contralateral healthy tonsil (HT) were obtained from 20 patients, analyzed by multiparameter flow cytometry, and assessed against a detailed HPV-status. Additionally, RNA-sequencing data from 38 TC samples available in the public database, The Cancer Genome Atlas (TCGA), were explored, focusing on the same leukocyte populations. HPV⁺ TC featured increased levels of CD8⁺ T-cells and antigen-presenting cells (cf. HPV⁻ TC and HT, respectively). In HPV⁺ TC, CD8⁺ T-cell frequencies correlated to DC levels independently of tumor stage, HPV 16 copy number, and E7 oncogene expression as well as frequencies of other leukocytes. Similarly, RNA sequencing data were explored by dividing the HPV⁺ TCs according to predefined CD8⁺ T-cell scores in silico. Higher levels of genes expressed by antigen-presenting cells and effector T-cells, such as immune checkpoints and cytokines, were detected in the CD8^HIGH HPV⁺ TC samples (cf. CD8^LOW HPV⁺ TC). In conclusion, CD8^HIGH HPV⁺ TC displays a unique inflammatory profile associated with increased effector T-cell functions and the presence of antigen-presenting cells in the tumor microenvironment. Further studies are warranted to assess if this information can be used on an individual basis to aid in prognosis and treatment decisions. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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12 pages, 1505 KiB

Open AccessArticle

Fatty Acid Receptor CD36 Functions as a Surrogate Parameter for Lymph Node Metastasis in Oral Squamous Cell Carcinoma

by Selgai Haidari, Matthias Tröltzsch, Thomas Knösel, Paris Liokatis, Anastasia Kasintsova, Marian Eberl, Florian Ortner, Sven Otto, Florian Fegg, Marko Boskov and Florian A. Probst

Cancers 2021, 13(16), 4125; https://doi.org/10.3390/cancers13164125 - 17 Aug 2021

Cited by 16 | Viewed by 2167

Abstract

Purpose: To investigate the expression pattern of CD36 in a patient population with oral squamous cell carcinoma (OSCC) and to correlate CD36 expression with clinical and histopathological parameters. The hypothesis was that CD36 expression correlates with the occurrence of lymph node metastasis. Methods: To address the study objectives, a retrospective cohort study was conducted. Study variables included demographic, histopathological and survival data. CD36 expression patterns were assessed by immunohistochemistry on tissue microarrays (TMA). Logistic regression analysis, survival analysis and Cox proportional hazards model were performed. Results: High CD36 expression correlated significantly with a higher T-status, grading and occurrence of lymph node metastasis. The logistic regression with binary N status as a dependent variable showed that high CD36 expression increased the chance for lymph node metastasis 45-fold (OR = 44.7, 95% CI: 10.0–316). Patients with high CD36 expression had lower probabilities of progression-free survival. CD36 had a small and non-significant independent influence on progression-free survival. Conclusions: CD36 is expressed in OSCC and correlates with tumor grading, T-status, and especially the occurrence of lymph node metastasis. CD36 may be useful for risk stratification regarding lymph node metastasis in OSCC. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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24 pages, 12232 KiB

Open AccessArticle

Electrochemotherapy with Mitomycin C Potentiates Apoptosis Death by Inhibiting Autophagy in Squamous Carcinoma Cells

by Maria Condello, Gloria D’Avack, Rosa Vona, Enrico Pierluigi Spugnini, Licia Scacco and Stefania Meschini

Cancers 2021, 13(15), 3867; https://doi.org/10.3390/cancers13153867 - 31 Jul 2021

Cited by 4 | Viewed by 2794

Abstract

We investigated the chemosensitizing effect of electroporation (EP), which, using electrical pulses, permeabilizes cancer cells to drugs. The study involved two human hypopharyngeal and tongue carcinoma cell lines. The surface and intracytoplasmic expression of P-gp were evaluated by flow cytometry, demonstrating that both lines were intrinsically resistant. After establishing the optimal dose of mitomycin C (MMC) to be used, in combination with EP, we showed, by both MTT assay and optical and electron scanning microscopy, the potentiating cytotoxic effect of EP with MMC compared to single treatments. Flow cytometry showed that the cytotoxicity of EP + MMC was due to the induction of apoptosis. In addition to verifying the release of cytochrome C in EP + MMC samples, we performed an expression analysis of caspase-3, caspase-9, Akt, pAkt, HMGB1, LC3I, LC3II, p62, Beclin1, and associated proteins with both apoptotic and autophagic phenomena. Our results were confirmed by two veterinary patients in whom the EP + MMC combination was used to control margins after the resection of corneal squamous carcinoma. In conclusion, we affirmed that the effect for which EP enhances MMC treatment is due to the inhibition of the autophagic process induced by the drug in favor of apoptosis. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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20 pages, 4533 KiB

Open AccessArticle

Combined In Situ Hybridization and Immunohistochemistry on Archival Tissues Reveals Stromal microRNA-204 as Prognostic Biomarker for Oral Squamous Cell Carcinoma

by Saroj Rajthala, Harsh Dongre, Himalaya Parajuli, Anjie Min, Elisabeth Sivy Nginamau, Arild Kvalheim, Stein Lybak, Dipak Sapkota, Anne Christine Johannessen and Daniela Elena Costea

Cancers 2021, 13(6), 1307; https://doi.org/10.3390/cancers13061307 - 15 Mar 2021

Cited by 11 | Viewed by 2982

Abstract

Micro-RNAs (miRs) are emerging as important players in carcinogenesis. Their stromal expression has been less investigated in part due to lack of methods to accurately differentiate between tumor compartments. This study aimed to establish a robust method for dual visualization of miR and protein (pan-cytokeratin) by combining chromogen-based in situ hybridization (ISH) and immunohistochemistry (IHC), and to apply it to investigate stromal expression of miR204 as a putative prognostic biomarker in oral squamous cell carcinoma (OSCC). Four different combinations of methods were tested and ImageJ and Aperio ImageScope were used to quantify miR expression. All four dual ISH-IHC methods tested were comparable to single ISH in terms of positive pixel area percentage or integrated optical density of miRs staining. Based on technical simplicity, one of the methods was chosen for further investigation of miR204 on a cohort of human papilloma virus (HPV)-negative primary OSCC (n = 169). MiR204 stromal expression at tumor front predicted recurrence-free survival (p = 0.032) and overall survival (p = 0.036). Multivariate Cox regression further confirmed it as an independent prognostic biomarker in OSCC. This study provides a methodological platform for integrative biomarker studies based on simultaneous detection and quantification of miRs and/or protein and reveals stromal miR204 as a prognostic biomarker in OSCC. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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21 pages, 7966 KiB

Open AccessArticle

Partial and Total Flap Failure after Fibula Free Flap in Head and Neck Reconstructive Surgery: Retrospective Analysis of 180 Flaps over 19 Years

by Michael Knitschke, Sophia Sonnabend, Christina Bäcker, Daniel Schmermund, Sebastian Böttger, Hans-Peter Howaldt and Sameh Attia

Cancers 2021, 13(4), 865; https://doi.org/10.3390/cancers13040865 - 18 Feb 2021

Cited by 28 | Viewed by 5474

Abstract

Fibula free flap (FFF) is widely used in head and neck reconstructive surgery and is considered as a standard and therapy of choice after ablative cancer surgery. The aim of this retrospective monocenter study was to determine the success rates of fibula free flaps for jaw reconstruction after ablative tumor surgery. The disease course of patients who underwent jaw reconstructive surgery with FFF from January 2002 to June 2020 was evaluated regarding the flap success rate. Flap failure was analyzed in detail and categorized into two groups: partial flap failure (PFF) and total flap failure (TFF). A total of 180 free fibular flaps were performed over the last 19 years and a total of 36 flap failures were recorded. TFF occurred in n = 20 (56.6%) and PFF in n = 16 cases (44.4%) cases. No statistically significant differences were found concerning patients’ age at flap transfer, sex, BMI, ASA-Score, preoperative non-virtual or virtual surgical planning (non-VSP vs. VSP), and time of reconstruction (immediately vs. delayed). Duration of hospitalization shows statistically significant differences between both groups (p = 0.038), but no differences concerning operating time and duration on Intensive Care Unit (ICU). Partial flap failure appears to be underreported in literature. Sub- and complete failure of the skin paddle leads to clinical complaints like uncovered bone segments and plate exposure. Partial or complete FFF failure lead to infections on the recipient site and prolonged wound healing and therefore may cause a delay of the beginning of adjuvant radiation therapy (RT). PFF of hard tissue can be induced by RT. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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28 pages, 1646 KiB

Open AccessReview

Emerging Role of Autophagy in the Development and Progression of Oral Squamous Cell Carcinoma

by Yomna S. Abd El-Aziz, Lionel Y. W. Leck, Patric J. Jansson and Sumit Sahni

Cancers 2021, 13(24), 6152; https://doi.org/10.3390/cancers13246152 - 7 Dec 2021

Cited by 8 | Viewed by 5548

Abstract

Autophagy is a cellular catabolic process, which is characterized by degradation of damaged proteins and organelles needed to supply the cell with essential nutrients. At basal levels, autophagy is important to maintain cellular homeostasis and development. It is also a stress responsive process that allows the cells to survive when subjected to stressful conditions such as nutrient deprivation. Autophagy has been implicated in many pathologies including cancer. It is well established that autophagy plays a dual role in different cancer types. There is emerging role of autophagy in oral squamous cell carcinoma (OSCC) development and progression. This review will focus on the role played by autophagy in relation to different aspects of cancer progression and discuss recent studies exploring the role of autophagy in OSCC. It will further discuss potential therapeutic approaches to target autophagy in OSCC. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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29 pages, 1324 KiB

Open AccessReview

Is There an Interplay between Oral Microbiome, Head and Neck Carcinoma and Radiation-Induced Oral Mucositis?

by Patryk Gugnacki and Ewa Sierko

Cancers 2021, 13(23), 5902; https://doi.org/10.3390/cancers13235902 - 24 Nov 2021

Cited by 17 | Viewed by 5442

Abstract

Head and neck carcinoma is one of the most common human malignancy types and it ranks as the sixth most common cancer worldwide. Nowadays, a great potential of microbiome research is observed in oncology—investigating the effect of oral microbiome in oncogenesis, occurrence of treatment side effects and response to anticancer therapies. The microbiome is a unique collection of microorganisms and their genetic material, interactions and products residing within the mucous membranes. The aim of this paper is to summarize current research on the oral microbiome and its impact on the development of head and neck cancer and radiation-induced oral mucositis. Human microbiome might determine an oncogenic effect by, among other things, inducing chronic inflammatory response, instigating cellular antiapoptotic signals, modulation of anticancer immunity or influencing xenobiotic metabolism. Influence of oral microbiome on radiation-induced oral mucositis is expressed by the production of additional inflammatory cytokines and facilitates progression and aggravation of mucositis. Exacerbated acute radiation reaction and bacterial superinfections lead to the deterioration of the patient’s condition and worsening of the quality of life. Simultaneously, positive effects of probiotics on the course of radiation-induced oral mucositis have been observed. Understanding the impact on the emerging acute radiation reaction on the composition of the microflora can be helpful in developing a multifactorial model to forecast the course of radiation-induced oral mucositis. Investigating these processes will allow us to create optimized and personalized preventive measures and treatment aimed at their formation mechanism. Further studies are needed to better establish the structure of the oral microbiome as well as the dynamics of its changes before and after therapy. It will help to expand the understanding of the biological function of commensal and pathogenic oral microbiota in HNC carcinogenesis and the development of radiation-induced oral mucositis. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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18 pages, 2596 KiB

Open AccessSystematic Review

Are Survival Outcomes Different for Young and Old Patients with Oral and Oropharyngeal Squamous Cell Carcinoma? A Systematic Review and Meta-Analysis

by Swagatika Panda, Neeta Mohanty, Saurav Panda, Lora Mishra, Divya Gopinath, Alkananda Sahoo, Sumanth Kumbargere Nagraj and Barbara Lapinska

Cancers 2022, 14(8), 1886; https://doi.org/10.3390/cancers14081886 - 8 Apr 2022

Cited by 8 | Viewed by 2342

Abstract

This systematic review and meta-analysis aims to address whether age can be a determinant of overall survival (OS), disease-free survival (DFS), recurrence, distant metastasis (DM) and second primary (SP) in surgically treated oral and oropharyngeal squamous cell carcinoma (OOPSCC). A total of 4981 cases and 44254 controls from 25 comparative observational studies were included in the analysis. A significantly better OS (matched subgroup analysis: OR 1.64; 95% CI 1.31–2.04, overall analysis: OR 1.48; 95% CI 1.09–2.01) was observed in young patients compared to older adults, with heterogeneity ranging from moderate to severe. Worse DFS (unmatched subgroup analysis OR 0.43; 95% CI 0.27–0.68) was observed in young patients compared to older adults with minimal to moderate heterogeneity. The frequency of recurrence (OR 1.49; 95% CI 1.10–2.02) and DM (OR 1.83; 95% CI 1.10–3.03) was significantly higher in the young patients, as found in unmatched and matched subgroup analysis, with the least heterogeneities. Young age can be considered as an independent prognostic factor for recurrence and distant metastases in OOP-SCC. Larger and methodologically robust observational studies with longer follow-up are needed to establish the definitive role of age as an independent prognostic factor on OS and DFS in OOPSCC. Full article

(This article belongs to the Special Issue Oral and Oropharyngeal Squamous Cell Carcinoma: Advances in Research)

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