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In contrast to HPV-negative HNSCC, in which TP53 (encoding p53) is frequently deleted or mutated, this gene is rarely altered in HPV-positive HNSCC, as p53 is eliminated by the action of E6 (ref.59). Assessment of voice, speech, and related quality of life in advanced head and neck cancer patients 10-years+ after chemoradiotherapy. Swartz, J. E. et al. Hypoxia induces the expression of HIF1α, a subunit of the transcription factor HIF1, which drives expression of a range of genes encoding proteins that promote angiogenesis (VEGF) and degradation of ECM (MMPs). Patients who survive their first HNSCC (especially HPV-negative HNSCC) remain at risk for development of a SPT of the upper aerodigestive tract for the rest of their lives. Zhang, Z., Filho, M. S. & Nor, J. E. The biology of head and neck cancer stem cells. Bauml, J. M. et al. E7 also interacts with and affects the levels and/or cellular activity of a number of other cell cycle regulatory proteins62,65. Proc. J. Med. 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Even when patients with HNSCC are treated in a multi-institutional chemoradiation clinical trial, the OS of those patients treated at centres that enrol more patients in trials in the USA was significantly longer than that of patients treated at institutions that enrol fewer patients235. Patterns of failure in high-metastatic node number human papillomavirus-positive oropharyngeal carcinoma. Head and neck squamous cell carcinoma (HNSCC) develops from the mucosal linings of the upper aerodigestive tract, comprising 1) the nasal cavity and paranasal sinuses, 2) the nasopharynx, 3) the hypopharynx, larynx, and trachea, and 4) the oral cavity and oropharynx. J. Immunother. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. 381, 1124–1135 (2019). Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Cancers of the oral cavity, including the mobile tongue, floor of the mouth, buccal mucosa, alveolar ridges, retromolar trigone and hard palate, classically present with a non-healing mouth sore or ulcer. Brooks, P. J. 35, 490–497 (2017). Alsahafi, E. et al. This paper describes the clinical trial that led to FDA approval of nivolumab for HNSCC. Squamous cell carcinoma of the head and neck (SCCHN) includes malignancies in the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, nasal cavity and salivary gland. Li, H. et al. HNSCC is characterized by genetic instability, with frequent loss or gain of chromosomal regions59. 357, 1705–1715 (2007). Components of this pathway are genetically altered in most HNSCC tumours, with frequent alterations in PIK3CA occurring by both mutation (14%) and gene amplification (16%). Alcohol 35, 187–193 (2005). 28, 2386–2398 (2017). Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Cell Biol. Onco Targets Ther. The treatment approach to every individual patient is guided by anatomical subsite, stage, disease characteristics, functional considerations and patient wishes. 45, 28 (2016). The biopsy method depends upon the location of the lesion. 91, 47–55 (2019). PubMed  I had anticipated this would take longer and I think it’s a benefit of having been irradiated on one side of the throat only. Rosin, M. P. et al. J. Head and Neck Imaging Head and Neck Squamous Cell Carcinoma: Diagnostic Performance of Diffusion-weighted MR Imaging for the Prediction of Treatment Response. For tumours with more advanced tumour or nodal stage, postoperative radiation or chemoradiation, guided by pathological risk factors, reduces the risk of recurrence and improves survival184,185. ISSN 2056-676X (online). Traditional staging of HNSCC using the tumour–node–metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Front. Science 333, 1154–1157 (2011). HPV infection accounts for the increasing incidence of HNSCC in younger people. Forastiere, A. HNSCC is a cancer of adults, with a median age at diagnosis of 66 years for HPV-negative HNSCC, 53 years for HPV-positive HNSCC and 50 years for EBV-positive HNSCC16,17,141. Coca-Pelaz, A. et al. Leon, X. et al. An ongoing randomized phase III clinical trial is investigating the safety and efficacy of atezolizumab (Tecentriq) as an adjuvant treatment after definitive local therapy in patients with high-risk, locally advanced squamous cell carcinoma of the head and neck (SCCHN), compared with placebo. Although a proportion of oral pre-malignant lesions (OPLs), which present as leukoplakia (white patches) or erythroplakia (red patches), progress to invasive cancer, the majority of patients present with advanced-stage HNSCC without a clinical history of a pre-malignancy. Mortal. J. Med. In tumour-infiltrating immune cells, hypoxia and HIF1 induce expression of pro-inflammatory and immune-modulatory cytokines and chemokines (such as IL-1β and TNF)73. J. Clin. Biol. Following histopathological confirmation of HNSCC, the staging evaluation includes the following procedures in all patients irrespective of HPV status: complete head and neck examination with direct inspection of the oral cavity and fibre-optic nasopharyngolaryngoscopy as indicated; cross-sectional imaging of the head and neck by CT or MRI to establish the extent of locoregional disease; and chest CT to rule out distant metastatic disease. Phys. A detailed analysis of 279 of these tumours, consisting of 243 HPV-negative and 36 HPV-positive tumours, revealed a high degree of genomic instability; tumours had an average of 141 CNAs and 62 chromosomal structural abnormalities (for example, fusions)59. 49, 216–223 (2013). Yang, X. et al. 167, 714–724 (2017). The disruption of RB1 function by E7 leads to a feedback upregulation of p16INK4A, and detection of p16INK4A expression is commonly used to classify oropharyngeal tumours as HPV-positive. Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. 17, 956–965 (2016). Cell Death Dis. The male to female ratio for HPV-positive HNSCC incidence ranges from three to six31, which is explained by higher rates of persistent oropharyngeal HPV infection among men despite similar prevalences of anogenital HPV infection32,33,34. Bledsoe, T. J. et al. The invisible enemy – how human papillomaviruses avoid recognition and clearance by the host immune system. Histopathology image of normal mucosa courtesy of R. Jordan, University of California San Francisco. Cancer 105, 41–46 (2003). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. PrimeView, Nature Reviews Disease Primers ), the Health and Medical Research Fund by the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region no. TP63 encodes two major isoforms, ΔNp63 and TAp63 (containing a truncated or complete transactivation (TA) domain, respectively), and is overexpressed in a majority of HNSCC tumours73. J. Clin. Disconcerting was the discovery that my treatment for a stage 1 cancer would be basically the same as for advanced cancer. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. https://doi.org/10.1093/jnci/djx042 (2017). GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter HNSCC cells with high levels of CD44 are capable of self-renewal, and CD44 levels in HNSCC tumours are associated with metastasis and a poor prognosis44,45. Cohen, E. E. W. et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Head and neck cancer survivorship care guideline: American Society of Clinical Oncology clinical practice guideline endorsement of the American Cancer Society guideline. There are three main types: Cancer Cell 27, 533–546 (2015). Epub 2011 Jul 28. Emerging insights into Wnt/β-catenin signaling in head and neck cancer. Arch. Microbial signatures associated with oropharyngeal and oral squamous cell carcinomas. Tobacco use, whether smokeless (chew or snuff) or combustible (cigarettes, cigars or pipes), and chewing of areca nut products including betel quid, are modifiable risk factors. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. and JavaScript. Cancer 18, 63 (2019). b | A poorly differentiated squamous cell carcinoma of the base of the tongue (×10). Predicting cancer development in oral leukoplakia: ten years of translational research. Zhang, Q. et al. This work was supported by the following: NIH R35CA231998 (J.R.G. d | A p16INK4A-negative oropharyngeal squamous cell carcinoma demonstrates minimal staining by the same anti-p16INK4A antibody, a staining intensity that is indicative of HPV-negative disease (×40). Oncol. Can public health policies on alcohol and tobacco reduce a cancer epidemic? The fogginess took about two months to clear, about as long as it took me to stop carrying a water bottle everywhere all the time. Clin. In a systematic review of minimally invasive transoral surgery to diagnostically assess an occult primary HNSCC tumour presenting as a cervical neck mass, the majority of tumours were p16INK4A-positive144. Clin. Cillo, A. R. et al. Ital. ), the Hong Kong Cancer Fund, Hong Kong SAR (V.W.Y.L. Cancer 125, 79–89 (2019). Geiger, J. L., Grandis, J. R. & Bauman, J. E. The STAT3 pathway as a therapeutic target in head and neck cancer: barriers and innovations. Human papillomavirus testing in head and neck carcinomas: guideline from the College of American Pathologists. Seiwert, T. Y. et al. Evidence-based interventions at the national policy level have been ranked according to cost-effectiveness by the WHO, which classifies the following four strategies as ‘best buys’: increased excise taxes on tobacco products; large graphic warnings on cigarette packages; comprehensive bans on tobacco advertising; and enforcement of a national, comprehensive, ban on smoking in public spaces161. Given the complex nature of everyday functions within the head and neck area, the inherent consequences of HNSCC and its treatment and the increasing choices of treatments have a large effect on the health-related QOL (HRQOL) of patients with HNSCC. Identifying gaps in research on rehabilitation for patients with head and neck cancer: a scoping review. 6, 249–256 (2012). In general, the high male to female ratios for HPV-negative HNSCC incidence reflect the sex-specific patterns of modifiable risk behaviours, including the use of the aforementioned tobacco, smokeless tobacco, areca nut, betel quid and alcohol21,24. Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer. Oncol. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Rubin Grandis, J. et al. Nature 578, 449–454 (2020). Hu, Z. et al. Fruit and vegetable intake and head and neck cancer risk in a large United States prospective cohort study. Biology of Head and Neck Squamous Cell Carcinoma. 8, 1027–1035 (2015). HNSCC is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018 (refs10,11,12) (Fig. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and accounts for approximately 650,000 new diagnoses and 350,000 cancer deaths every year (Parkin, et al., 2005). ), Research Impact Fund R4015-19F and R4017-18 (V.W.Y.L. If tumours are neglected, patients can present with dyspnoea (difficulty breathing) and, ultimately, airway obstruction, prompting tracheostomy. Cell Biol. Castellanos, E. & Baxi, S. S. Letting the GENIE out of its bottle: examining the potential of real-world clinicogenomic data. Non-smokers who develop HPV-positive HNSCC generally survive their head and neck cancer, and clinical strategies to date have focused on identifying treatments that are associated with reduced morbidity. Epub 2011 Jul 28. Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. No screening strategy has proved to be effective, and careful physical examination remains the primary approach for early detection. J. Clin. However, to date, only a subset of patients with HNSCC are expected to respond to immune checkpoint inhibitors, and reliable predictive biomarkers are needed. Peyser, N. D. et al. Health-related quality of life before and after head and neck squamous cell carcinoma: analysis of the Surveillance, Epidemiology, and End Results–Medicare Health Outcomes Survey linkage. D’Cruz, A. K. et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. Lab. Oncol. Epub 2014 Apr Squamous cell carcinoma of the head and neck (HNSCC) is a relatively common human cancer characterized by high morbidity, high mortality, and few therapeutic options outside of surgery, standard cytotoxic chemotherapy, and radiation. Rowhani-Rahbar, A. et al. Nature 517, 576–582 (2015). However, the average latency period of 10–30 years from initial oral infection to ultimate diagnosis of p16INK4A-positive oropharyngeal cancer means that risk factors might be remote143. The TME of HNSCC tumours also includes innervating neurons derived from the peripheral nervous system. U.S. Department of Health and Human Services https://www.hhs.gov/sites/default/files/2020-cessation-sgr-full-report.pdf (2020). Analysis of plasma Epstein-Barr virus DNA in nasopharyngeal cancer after chemoradiation to identify high-risk patients for adjuvant chemotherapy: a randomized controlled trial. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Head Neck Surg. J. Clinical practice guideline: evaluation of the neck mass in adults. The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices recommends HPV vaccination for all children and adults aged 9–26 years166. Google Scholar. Mol. 68, 394–424 (2018). Tsang, C. M., Lui, V. W. Y., Bruce, J. P., Pugh, T. J. After a diagnosis of recurrent disease or distant metastasis, patients with disease that is amenable to local therapy receive resection, radiation or limited-volume irradiation and are then subject to observation. In other parts of the world, head and neck cancer is much more prevalent. HNSCC tumours routinely stain with pancytokeratin antibodies and markers of squamous differentiation, including antibodies to cytokeratin 5, cytokeratin 6 and p63 (ref.148). Oncol. 24, 1178–1191 (2018). Cancer Res. 91, 1194–1210 (1999). Australia’s experience. Prevalence of oral HPV infection in the United States, 2009–2010. How are genetic conditions treated or managed? Although the mechanisms responsible for the unique proclivity of patients with Fanconi anaemia to develop HNSCC remain unknown, alterations in Fanconi anaemia pathway genes are likely to have a role. Single-cell transcriptomic analyses of primary and metastatic HNSCC tumours revealed that cells with p-EMT are localized to the leading edge of tumours and that p-EMT can serve as an independent predictor of metastasis, tumour grade and detrimental pathological features137. 7, 77–82 (2006). Phys. Advances in minimally invasive resection, including transoral robotic or laser resection and larynx-preserving partial laryngectomy, as well as improved reconstructive techniques, have extended the indications for primary surgical management in the hands of highly specialized head and neck surgical oncologists180,181. The main factors were having a dry mouth and being foggy-brained. Morb. The FDA approval of immune checkpoint inhibitors in 2016 for the treatment of recurrent or metastatic disease, and for front-line treatment of inoperable or metastatic cancer in 2019, definitively altered the landscape of HNSCC therapy and clinical trial opportunities. CAFs have a key role in HNSCC progression and are distinguished from normal fibroblasts by a persistent state of activation and expression of α-smooth muscle actin (αSMA)98. Analysis of plasma Epstein-Barr virus DNA to screen for nasopharyngeal cancer. J. Med. Pathol. The number of men with HPV-positive HNSCC has now surpassed the number of women with HPV-associated cervical cancer in the USA238, suggesting that without widespread HPV vaccination, HPV-positive HNSCC could reach epidemic proportions. Currently, two doses of the vaccine are recommended for children aged 15 years or younger, whereas three doses are recommended for those older than 15 years. 51, 557–564 (2015). Michaud, D. S. et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. 157, S1–S30 (2017). Wang, Z. et al. As such, patients with a first HPV-negative HNSCC are at high risk of a SPT of the upper aerodigestive tract, including in the head and neck, oesophagus or lung159. Oncol. Loss of p53 drives neuron reprogramming in head and neck cancer. Arch. Head Neck 42, 456–466 (2020). Defining a global research and policy agenda for betel quid and areca nut. 1862, 153–162 (2019). Risk of onset of second neoplasms and successive neoplasms in patients with a head and neck index tumour. Int. JCI Insight 1, e89829 (2016). Association of five Snps in cytotoxic T-lymphocyte antigen 4 and cancer susceptibility: evidence from 67 studies. Cancer Discov. Eur. Cancer Discov. Cancer Prev. Wang, Z., Valera, J. C., Zhao, X., Chen, Q. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies. Department of Otolaryngology-Head and Neck Surgery, University of California at San Francisco, San Francisco, CA, USA, Department of Medicine, Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA, Department of Otolaryngology-Head and Neck Surgery, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, Department of Medicine-Hematology/Oncology, University of Arizona, Tucson, AZ, USA, You can also search for this author in Squamous-cell carcinoma is a cancer of the squamous cell – a kind of epithelial cell found in both the skin and mucous membranes. Br. My appetite went down as my mouth went dry and my sense of taste slipped away. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. Copy link. (2021), Nature Reviews Disease Primers | Induction chemotherapy may also be used to control disease when curative surgery cannot immediately be accessed, as has been the case in areas with surging incidence of COVID-19 (ref.200). USA 111, 1114–1119 (2014). For patients who experience immune-related adverse events, such as pneumonitis, colitis or other organ injury, treatment interruption and systemic corticosteroids are indicated208. Neoplasia 11, 583–593 (2009). Chen, A. M. et al. Hutcheson, K. A. et al. In addition, HNSCC cells with CSC properties express elevated levels of the stem cell markers OCT3, OCT4, SOX2 and NANOG, with the levels of these proteins correlating with tumour grade in oral cancers47. & Grandis, J. R. 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Surgery is commonly used for oral cavity cancers, whereas radiation might be more commonly employed for pharyngeal and laryngeal cancers. Mortal. J. Transl Med. Ferris, R. L. et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. Fang, J. et al. Head Neck 29, 564–572 (2007). 1. Worden, F. P. et al. Taylor, M. H. et al. Lewis, J. S. Jr. et al. It is likely that a series of changes in multiple genes is involved in the development and progression of HNSCC. However, given the improved outcome in most patients with HPV-positive HNSCC, they are less likely to receive these immune checkpoint inhibitors as part of standard of care than patients with HPV-negative HNSCC. Lee, V. H. et al. 18, 873–898 (2020). A well-differentiated tumour closely resembles the stratified epithelium, with mature-appearing cells organizing into layers with irregular keratinization, most classically manifesting as a ‘keratin pearl’ (Fig. 55, 24–30 (2016). Similarly, MDSCs and Treg cells recruited to the HNSCC TME express PDL1 and another immunosuppressive molecule, cytotoxic T lymphocyte antigen 4 (CTLA4), respectively. Gillison, M. L. et al. Tobacco and alcohol consumption are the high-risk factors that occur most widely geographically. Clinical update on head and neck cancer: molecular biology and ongoing challenges. Heading. and D.E.J. Genetic and epigenetic alterations result in decreased tumour cell levels of human leukocyte antigen (HLA) and defects in antigen processing, leading to decreased recognition and cytolysis of tumour cells113,114. Shopping. Oncol. ), NET-QUBIC–Dutch Cancer Society grant VU 2013-5930 (C.R.L. J. Natl Cancer Inst. Proposed modifications and incorporation of plasma Epstein-Barr virus DNA improve the TNM staging system for Epstein-Barr virus-related nasopharyngeal carcinoma. A subgroup analysis showed improved survival in all age groups except in older patients (>75 years of age) and for all anatomical sites except the larynx, where survival was stagnant. Lyhne, N. M. et al. Considering the concept of field cancerization, the development of SPTs may reflect distinct CSCs arising from independent oncogenic transformations. Similarly, OCT3, OCT4 and NANOG promote invasiveness of HNSCC cells and their presence may serve as a predictor of metastasis45. Tobacco consists of more than 5,000 different chemicals, of which dozens have been shown to have carcinogenic activity. Br. Brooks, J. M. et al. Users with questions about a personal health condition should consult with a qualified healthcare professional. Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Mitigating the toxicities associated with standard of care, including platinum chemotherapy and radiation, for these patients remains an important objective. Phys. Clin. Substantial progress has been made over the past decade in the molecular characterization of both HPV-positive and HPV-negative HNSCC, culminating in TCGA59,71,72. Decreased use of tobacco products, improved oral health and widespread HPV vaccination should help reduce the global incidence of HNSCC42. Whereas the indications for prophylactic HPV vaccination were established from the results of randomized, placebo-controlled trials evaluating the burden of anogenital HPV infections, the effectiveness against oral HPV infection has been analysed retrospectively in three populations. Ha, P. K. & Califano, J. Oncol. In smokeless tobacco, nitrosamines are the dominant carcinogen, whereas the carcinogens in areca nut and betel quid are poorly defined55. Quality of life, cognitive, physical and emotional function at diagnosis predicts head and neck cancer survival: analysis of cases from the head and neck 5000 study. Pathological features indicative of increased risk of recurrence include extra-nodal extension, close or involved surgical margins, or perineural invasion; when these are present, administration of high-dose cisplatin chemotherapy concurrently with radiation further improves disease-free survival and impacts survival in the highest risk groups184,185. The strongest risk factors for developing this form of cancer are tobacco use (including smoking or using chewing tobacco) and heavy alcohol consumption. Shah, F. D. et al. Specific genetic events have been found to be enriched at each stage of progression and are indicated. Oral cavity tumours are often diagnosed at an early stage owing to the patient’s self-identification of the mass lesion and symptoms that interfere with the fundamental functions of eating and speaking, such as pain with chewing or dysarthria (difficulty speaking). N. Engl. J. Med. HNSCC tumours exhibited frequent mutation of CDKN2A (22% of tumours) and TP53 (72% of tumours). Expression of E-cadherin and vimentin correlates with metastasis formation in head and neck squamous cell carcinoma patients. N. Engl. The risk of second primary tumors in head and neck cancer: a systematic review. Cancer 144, 1941–1953 (2019). Med. J. Med. Chemoselection as a strategy for organ preservation in patients with T4 laryngeal squamous cell carcinoma with cartilage invasion. 29, 4294–4301 (2011). Talamini, R. et al. 14168517 (V.W.Y.L. Califano, J. et al. Oncol. Sterz, C. M. et al. U.S. Department of Health and Human Services, squamous cell carcinoma of the head and neck. New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development. 92, 1093 (2019). 31, 204–211 (2006). Oral Pathol. Clin. Cell Physiol. Stable integration of the viral genome into the host genome, and the concerted action of HPV E6 and E7 proteins on cellular p53 and RB levels, respectively, acts to promote cellular transformation. An emerging field of study is the role of the microbiota in the HNSCC TME, particularly in oral cancer. Lim AM, Do H, Young RJ, Wong SQ, Angel C, Collins M, Takano EA, Corry J, Immunity 52, 183–199.e9 (2020). & Wang, B. Y. Other risk factors include ageing, poor oral hygiene and diets lacking in vegetables27,28. Clin. Ann. Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma. Neoplasia 15, 461–471 (2013). Squamous cell carcinoma is a cancer that arises from particular cells called squamous cells. 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