Manuscript DoiAdvance : 10.1093/ecco-jcc/jjv122 Journal of Crohn's and Colitis Access published July 10, 2015
REVIEW "Oral cancer and oral precancerous lesions in inflammatory bowel
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diseases, a systematic review”
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Short running title: Oral cancer and IBD
Konstantinos H. Katsanos1, Giulia Roda1, Alexandre Brygo2, Emmanuel
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Delaporte3, Jean-Frédéric Colombel1.
1
The Leona M. Harry B. Helmsley Inflammatory Bowel Disease Center, The
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Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at
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Mount Sinai, One Gustave Levy Place, New York, 10029 NY, USA. 2
Department of Stomatology, Centre Hospitalier Régional Universitaire de
3
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Lille 2, avenue Oscar Lambret - 59037 Lille Cedex, France. Department of Dermatology, Centre Hospitalier Régional Universitaire de
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Lille 2, avenue Oscar Lambret - 59037 Lille Cedex, France.
Abbreviations used in the text: IBD: inflammatory bowel disease, CD: Crohn’s disease, UC: ulcerative colitis, anti-TNFa: antibody to tumor necrosis factor alpha, IS: immunosuppressant(s) Conflict of interest and funding: None
Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
Manuscript Doi : 10.1093/ecco-jcc/jjv122
Author responsible for correspondence and reprints: Jean-Frédéric Colombel, MD
The Henry D. Janowitz Division of Gastroenterology Icahn School of Medicine at Mount Sinai
Phone:(212)241-4299, Fax: (212) 426-5099
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e-mail: [email protected]
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One Gustave Levy Place, New York, 10029 NY, USA.
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The Leona M. and Harry B. Helmsley Inflammatory Bowel Disease Center
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Abstract Oral cancer is historically linked to well-known behavioral risk factors such as tobacco smoking and alcohol consumption. Other risk factors include age over forty, male sex, several dietary factors, nutrition deficiencies, viruses,
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sexually transmitted infections, human papillomavirus, chronic irritation and possibly genetic predisposition. Precancerous lesions in the oral cavity
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include leukoplakia, erythroplakia and lichen planus. Histology of oral cancer varies largely but the great majority is squamous cell carcinomas.
Epidemiological studies and cancer registries have shown a consistently
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increased risk of oral malignancies in kidney, bone marrow, heart or liver transplantation, in graft versus host disease and in patients with HIV infection.
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Because of the increasing use of immunosuppressive drugs in patients with inflammatory bowel disease it is useful to more accurately delineate the
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consequences of chronic immunosuppression to the oral cavity. Oral cancer and pre-cancerous oral lesions in patients with IBD have been scarcely
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reported and reviews on the topic are lacking. We conducted a literature search using the terms and variants of all
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cancerous and precancerous oral manifestations of inflammatory bowel diseases. By retrieving the existing literature it is evident that patients with
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IBD belong to the high-risk group of developing these lesions, a phenomenon strengthened also by the increasing HPV prevalence. Education on modifiable risk behaviors in patients with oral cancer is the cornerstone of prevention. Oral screening should be performed for all IBD patients, especially those who are about to start a immunosuppressant or a biologic.
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Key words: Inflammatory bowel disease, Crohn's disease, ulcerative colitis, oral cancer, oral malignancy, oral precancerous lesions, immunosuppressant,
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azathioprine, biological therapies, anti-TNFa.
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INTRODUCTION Epidemiological studies and cancer registries have shown a consistently increased risk of head and neck malignancies in patients undergoing kidney, bone marrow, heart or liver transplantation, in graft versus host disease and in
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patients with HIV infection although the calculated risk differs markedly between studies essentially because of differences in methodologies and selection of
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patients. Skin, lip, buccal cavity and tongue cancers, lymphomas, melanomas and Kaposi's sarcomas, are the main types of cancer reported in these patients.1 Oral cancer is historically linked to well-known behavioral risk factors such as
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tobacco smoking and alcohol consumption. Other main risk factors are age over 40 and male sex.2 In addition, several dietary factors, nutrition deficiencies,
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viruses, sexually transmitted infections, chronic irritation and possibly genetic predisposition have been also associated with oral cancer.3
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Substantial evidence has been mounting that human papillomavirus (HPV) infection is playing an increasing important role in oral cancer. In fact, HPV
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infection is recognized as one of the major causes of infection-related cancer worldwide. Indeed, strong evidence for a causal etiology with HPV has been
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stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx including base of the
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tongue and tonsils. Of the estimated new cancers occurring each year worldwide, 4.8% are attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries.4 Extra-intestinal malignancies in inflammatory bowel disease (IBD) have been linked with various aetiologies except of the disease itself. Oral cancer and pre-
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cancerous oral lesions in patients with IBD have been scarcely reported and reviews assessing the magnitude of this problem are lacking. Herein, we review systematically all data on epidemiology, aetiopathogenesis, and risk factors of oral malignant and pre-malignant lesions and conditions
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associated with IBD, and we provide a comprehensive guide for clinicians regarding the principles of optimal therapeutic management of these challenging
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extra-intestinal malignancies in patients with IBD.
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SEARCH STRATEGY
A comprehensive literature search using the terms and variants of all
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cancerous and precancerous oral manifestations of inflammatory bowel diseases (ulcerative colitis, Crohn’s disease) was performed in January 2015
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within Pubmed, Embase and Scopus and was restricted to human studies (1946 to 2015, January) and EMBASE (1947 to January, 2015). Studies were included if they were published in any language and if related to oral
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malignant or pre-malignant lesions or conditions with special focus on IBD.
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Additionally, references from relevant literature were hand searched (search
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strategy is available in the Appendix).
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EPIDEMIOLOGY AND PATHOGENESIS OF ORAL CANCER
The term oral cancer refers to cancers of the mucosal surfaces of the lips, floor of mouth, tongue, buccal mucosa, lower and upper gingival, hard palate and
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retromolar trigone.5 Head and neck cancer represent the sixth most common malignancy worldwide while the annual incidence of oral cancer exceeds 3,000,000 new cases.
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Several aetiopathogenetic mechanisms have been suggested so far [Figure 1]
but the pathogenesis of oral cancer still needs further elucidation. There are several reports on mucosal immunodeficiency in smokers and on changes of the
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saliva in patients under immunosuppressive or anti-neoplastic therapy.6 Reduced saliva volume and change in saliva constituents may affect epithelial
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maintenance and repair, the physiology of the oral microflora, and the interaction between the oral flora and the epithelium.7 Chronic oral candidiasis has been
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also suggested as a potential pathogenetic mechanism especially in patients with
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prolonged steroid use.8
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RISK FACTORS OF ORAL CANCER
Risk factors for oral cancer can be divided into precancerous lesions and precancerous states such as conditions related to life style (i.e smoking, alcohol consumption), to medical therapy or to carriage of oncogenic viruses.
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a. Precancerous lesions Diagnosis of oral cancerous lesions is generally easy but early recognition of precancerous lesions and precancerous conditions is often challenging, especially in patients that belong to high risk groups. It is important to
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underline here that most oral cancers do not develop from pre-existing precancerous lesions.
Precancerous lesions include chronic lesions of the oral cavity on which
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cancer of the oral cavity is known to develop with low to high probability. 9 These include: leucoplakia, oral lichen planus, erythroplakia, papillomatous lesions, actinic cheilitis, submucosal fibrosis, keratotic candidosis, and tertiary
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syphilis. The precancerous states include cancers occasionally observed in the oral cavity during any kind of immunosuppression or other conditions
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related to therapy and to lifestyle.10
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Oral lichen planus
Oral lichen planus is a common disease of unknown aetiology affecting oral
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mucosae. It is characterized by T-cell mediated chronic inflammation and has
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been clinically associated with development of oral squamous cell carcinoma although the risk for neoplastic change seems low [Figure 2].11
Malignant
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transformation is seen in less than 2% of the patients within 10 to 15 years. 12 Histologically the oral lichen planus does not differ from the oral lichenoid reactions which are lesions mostly found in contact with amalgam restorations. In such cases a causative treatment with replacement of the amalgam is recommended. Leukoplakia, erythroplakia and erythroleukoplakia
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The most frequent causes of leukoplakia and erythroplakia are smoking, chewing tobacco and poorly fitting dentures. Most cases of leukoplakia do not develop into cancer but some leukoplakias are either cancerous when first found or have precancerous changes. Erythroplakia and erythroleukoplakia are less common but
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are usually more serious.13
Oral hairy leukoplakia has been suggested as a marker for severe immunosuppression and was initially described in immunocompromised men
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infected with the human immunodeficiency virus (HIV)14 but has also been
described in other iatrogenic instances such as in immunocompromised 15, and
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transplanted16 patients.
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b. Precancerous states The role of immunosupression
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Immunosuppressive drugs seem to substantially contribute to skin/lip and oral cancer development after organ transplantation, either as a result of
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immunosuppression or through specific carcinogenic mechanisms [Appendix
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Table 1]. Prolonged immunosuppression for multiorgan chronic graft-versus-host disease
increases
the
risk
of
oral
cancer17
while
double
or
of
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immunosuppression also increases this risk.18 In addition, the extent
triple
immunosuppression as expressed by lower total leukocyte count was related to an increased risk of hairy leukoplakia in kidney transplant patients.19 Thiopurines Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) may promote cancers by various mechanisms including carcinogenic mutations of cell DNA,
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impaired immunosurveillance of tumour cells, impaired number or function of immune cells chronically infected by Epstein-Barr Virus (EBV) or HPV and several others. Methotrexate
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In general, the use of MTX monotherapy or in combination with other
immunosuppressants has been reported to be safe in rheumatology20 or in
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patients with psoriasis.21 Of note, MTX has been used as anti-neoplastic therapy for head-neck cancers and for oral florid papillomatosis.22 Corticosteroids
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A single study suggested that the use of oral glucocorticoids may increase the risk of skin cancers and in particular, among patients other than organ transplant
Biological therapies
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recipients, but this has to be further confirmed.23
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Tumour necrosis factor-alpha is a cytokine produced by activated T cells and macrophages determining in vitro a necrotizing effect on tumor cells. Blocking
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TNF-alpha has therefore been hypothesized to increase the overall cancer risk.
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Rare cases of oral cancer or precancerous lesions on anti-TNFa and biological therapies have been reported in non-IBD patients [Appendix Table 2] including
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also one case of oral candidiasis in a patient with sarcoidosis on infliximab. 24 Another study on the influence of TNF-α blockers on the oral prevalence of opportunistic microorganisms in patients with ankylosing spondylitis showed that anti-TNF-α therapy could not be correlated with increased counts of microorganisms.25
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Studies including patients with rheumatoid arthritis on anti-TNFa therapies did not find any evidence for an excess cancer risk on TNF-α antagonists but according to the authors an excess cancer risk after several years of exposure cannot be ruled out.26
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The past few years have seen an increased interest in the implications of integrin
receptors in cancer biology and tumor cell aggression. No case of oral cancer
during anti-integrin therapy has been so far reported. Long-term risk assessment
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of oral cancer in patients on biological requires observational studies and safety-
Oncogenic viruses Human papillomavirus (HPV)
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assessments using randomized controlled trials meta-analyses.
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A rise in incidence of oropharyngeal squamous cell cancer in non-transplanted white men younger than 50 years who have no history of alcohol or tobacco use
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has been recorded over the past decade and this was associated with human papillomavirus (HPV) 16 infection. Of interest, the biology of HPV-positive
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oropharyngeal cancer is distinct with P53 degradation, retinoblastoma RB
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pathway inactivation, and P16 up regulation. By contrast, tobacco-related oropharyngeal cancer is characterized by TP53 mutation.27 Sometimes the term
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«oropharynx» introduces a confusion as, according to some physicians, it is meant to include
also the buccal cavity. In fact, the oropharynx includes
everything that lies behind the tonsils. So, from one hand it is right to support that oropharyngeal cancers are linked to HPV, by the other hand in the buccal cavity, the role of HPV is debatable. Thus, a clear separation for the role of HPV
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regarding carcinogenesis in the buccal cavity and the oropharynx has to be evaluated. Epstein-Barr virus (EBV) Epstein-Barr virus (EBV) is classically associated with Burkitt's lymphoma, B-cell
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lymphoproliferative syndromes, nasopharyngeal carcinoma, Hodgkin's disease, T-cell lymphomas, thymic lymphoepithelial carcinoma, gastric carcinoma and oral
hairy leukoplakia.28 EBV presence and oral manifestations have been also
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reported in patients who had undergone bone marrow transplantation 29 and heart
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transplantation.30
TAXONOMY OF ORAL CANCEROUS LESIONS
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Taxonomy of oral cancerous lesions includes location, histology and HPV
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positivity. Taxonomy by location Lip cancer
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A case of squamous cell carcinoma of the lip associated with adalimumab
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therapy for ankylosing spondylitis31 has been reported so far. Although the increased risk of non melanoma skin cancer including dysplastic and malignant
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lip lesions in immunosuppressed solid organ transplant patients is well known 32, the association with inflammatory bowel disease remains unknown. Buccal cancer Among the most common malignancies observed in transplant recipients were non melanomatous skin cancers and squamous cell cancers of the buccal cavity.33
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Gingival cancer Gingival cancer can be primary or metastatic. The most common primary sources of metastatic tumours to the oral region are the breast, lung, kidney, bone, colon while choriocarcinoma and hepatocellular carcinoma metastatic to the maxillary
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gingival may also occur.34-35 Tongue cancer
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In transplant recipients, erythroplakia of the tongue36, lymphoproliferative disease37 and squamous cell tongue carcinoma have been described.38
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Taxonomy by histology and HPV positivity
Histology of oral cancer varies largely but more than 9 of 10 cancers of the
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oral cavity and oropharynx are squamous cell carcinomas [Figure 3]. There are also other types including non-squamous, lymphoma, melanoma [Figure
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4], non-melanoma, metastatic and other rare types such as Kaposi sarcomas [Figure 5].39 Finally, characterization of oral cancers by HPV positivity is
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important for disease diagnosis and prognosis.
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ORAL CANCER PROGNOSIS Prognosis of oral cancer differs significantly among specific oral locations, with
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cancer of the lip, for example, having a much better prognosis compared to a cancer at the base of tongue or on the gingiva. 3 Prognosis of intra-oral cancer is generally poor, with a five-year survival less than 50 percent. Especially in post transplant oral tumors outcomes are worse compared to the normal population. Local recurrences occur in a significant percentage of patients, while distant metastases are less frequent. Prognosis correlates mainly with the size of the
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lesion and the nodal status at the time of diagnosis.40 Of importance, HPV positivity is correlated with better cancer outcomes. A significant association of p16 (INK4a) overexpression with improved survival in young patients with squamous cell cancers of the oral tongue has also been demonstrated. However,
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EPIDEMIOLOGY OF ORAL CANCER IN IBD
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p16 (INK4a) overexpression was not a reliable predictor of HPV positivity.41
The incidence and prevalence of oral cancerous and pre-cancerous lesions in IBD is currently unknown. It could also be possible that oral cancers in IBD
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were grouped together in the past within the upper digestive track cancers or head and neck cancers group, thus overshadowing the exact magnitude of
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the problem. Moreover, no routine oral screening for IBD patients, especially for those who are about to start an immunosuppressant or a biological therapy
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is performed or is advised so far.
Direct or indirect information for the occurrence of oral malignancies in IBD
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were extracted -with every possible caution and after meticulous search and analysis- from large cohort studies, clinical trials and rare case reports [Table
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1]. According to this data the prevalence of oral cancer in IBD seems probably to be low as the risk for oral cancer in IBD has been estimated to range from
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1.08 (0.31-3.70) to 1.78 (0.37, 5.21).42-50 Taking into account all above limitations in the oral cancer risk calculations, it
is evident that well-designed prospective studies are urgently needed to clearly assess the real magnitude of the risk of oral cancer in IBD and to possibly identify high-risk groups of patients needing close surveillance.
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RISK FACTORS OF ORAL CANCER IN IBD
a. Precancerous lesions
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Although the prevalence of these lesions has been reported to be significantly increased in transplant recipients, they have been rarely reported in patients with
IBD [Table 2]. Successful adalimumab use for oral lichen planus has been
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reported51 and there are also reports on paradoxical triggering of erosive lichen
planus during infliximab treatment52-53 and of de novo oral lichen planus occurence after certolizumab pegol treatment in a patient with Crohn's disease. 54
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Oral hairy leukoplakia has been once reported in a patient with ulcerative
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precancerous states.56
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colitis.55 Of note, precancerous lesions have to be distinguished from
b. Treatment-related risk factors
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IBD patients receiving immunosuppressive therapy are theoretically at an increased risk of developing extraintestinal malignancies.57-59 However, the exact
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magnitude of this risk is currently unknown as it may occur in cancers where
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absolute numbers may be low but relative risk may be high. Thiopurines So far, two cases of oral cancer during azathioprine (AZA) therapy have been reported in IBD, both in patients with Crohn’s disease. The first was a case of a 39-year-old non-smoking male with Crohn's disease who had been treated for 3 years with azathioprine and developed a lingual ulcer. Biopsy revealed
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squamous cell carcinoma of the tongue.60 The second one was a case of a 33year-old Caucasian woman with Crohn's disease treated with azathioprine for 9 years who developed an ulcerated lesion at the right superior retromolar trigone and in which subsequent biopsy revealed a squamous cell carcinoma. 61
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In general, in patients with IBD, azathioprine use was associated with an increased risk of overall cancer (rate ratio = 1.41, 95% confidence interval: 1.15, 1.74), whereas former use of azathioprine (rate ratio = 1.02, 95% confidence
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interval: 0.83, 1.25) or increasing cumulative received doses were not. 62 Patients with IBD with a history of cancer are at increased risk of developing any new or recurrent cancer, with a predominant incidence of new cancers. Treatment with
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immunosuppressants has no overall major impact per se on this risk. 63
It should be emphasized that, the doses of immunosuppression used in
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transplanted patients are significantly higher than those used in IBD, so it is
Methotrexate
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difficult to suggest a parallel degree of risk.
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No cases of oral cancer during methotrexate (MTX) therapy for IBD has been reported so far. In addition, there is no study in the literature supporting an
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excess risk of cancer in IBD patients who are exposed to methotrexate. Calcineurin inhibitors
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Cyclosporin A and tacrolimus are used in a minority of patients with IBD and most of the time on a short-term basis. No safety data are available on the risks of cancer associated with the use of these drugs in IBD and no case of oral cancer has been so far reported during or after the use of these two drugs. Corticosteroids There is no report on oral cancer under corticosteroid use in IBD patients so far.
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Biological therapies Several studies have investigated the cancer risk associated with anti-TNFs use in IBD but none of them has focused on oral cancer risk. One limitation of these studies is that most of the IBD patients treated with anti-TNFs have either a
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concurrent or a past use of thiopurines, thus making difficult to evaluate the cancer risk related to anti-TNFs alone. Current evidence suggests that the use of anti-TNFs alone in IBD is not associated with a significant increase in the overall
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cancer risk. There are also scarce reports on oral cancer during biological
therapy in other autoimmune-based diseases.64-65 No case of oral cancer during
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anti-integrin therapy in IBD has been reported so far.
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TREATMENT OF ORAL CANCER IN IBD PATIENTS Conventional treatment of oral cancer
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Conventional treatment approaches of oral cancer include surgery, radiotherapy and adjuvant systemic chemotherapy. Various combinations of these approaches
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may be selected depending on the disease presentation and pathological findings. Treatment of oral precancerous lesions includes surgical excision or/and
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topical application of calcineurin inhibitors but therapy has to be individualized. 66
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Modification of immunosuppression Management of immunosuppression in patients with IBD diagnosed also with oral cancer
or
precancerous
lesions
is
challenging.
Modification
of
immunosuppression has been proved to be important in those patients but the detailed principles of management of immunosuppression after cancer diagnosis are debatable.
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Changing the immunosuppressive regimen from azathioprine to cyclosporin or vice versa does not seem to relieve skin predisposition to cancer.67 Apart from immunosuppressive therapy modifications, exposure to sunlight and infection with human papillomaviruses as well as oral screening for preexistent occult
Special oncologic issues and prevention of recurrence
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carcinomas are believed to represent the most important preventive measures.
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Primary or metastatic tumours to the oral region have to be always excluded
before starting immunomodulators or biological therapies in IBD patients. In
has to be set on individual basis.
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cases with documented oral precancerous lesions the prioritization of treatment
Oral surveillance strategies in patients exposed to immunosuppressants and
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biological is mandatory before initiation and during any therapy. Annual examination by dermatologist, stomatologist and ENT/oncologist specialist is
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mandatory in those patients. Based on the examination of specialists, risk assessment according to the individual risk factors (i.e smoking, precancerous
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lesions) and tailored case by case surveillance strategy defined for each patient
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will be performed.68
Management decisions regarding immunosuppression in IBD patients with a
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cancer are best made in a multidisciplinary fashion and on a case by case basis, taking into account the natural history of the cancer (organ of origin, stage, histological type and prognosis). This should include the opinion of the oncologist, the time from completion of cancer treatment, the severity of the IBD and the expected impact of the immunosuppressant on the previous cancer. It
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seems reasonable to withhold immunosuppressants during the treatment of active oral cancer. Within 2 years after completing cancer treatment, 5- aminosalicylates, corticosteroids, antibiotics, nutritional therapy and surgery should form the
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foundation of IBD treatment. However, if these treatment modalities are
ineffective in a patient with severe IBD, then immunosuppressive therapy should be considered as rescue therapy. If a tumour has an intermediate to high risk of an
interval
of
5
years
is
preferable.
In
all
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recurrence,
cases,
if
immunosuppressive therapy is resumed, a step-up approach should be
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considered, starting with monotherapies.
Anti-TNF therapy is contraindicated in patients with a history of lymphoma and careful consideration should be given to initiating anti-TNF therapy in those with a
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history of oral cancer.69 The use of anti-TNFa therapies in IBD patients with prior oral malignancy remains a challenging topic to address because, in general,
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patients with prior oral malignancy are not likely to be prescribed a TNF inhibitor at least on a short-term follow up.70
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Although there are few data regarding the impact of steroids on cancer, the
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general consensus is that corticosteroids are the safer option although anti-TNFs may be a useful back-up plan.
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Overall, the risks associated with biologic agents should be weighed against their potential benefits in patients with previous oral malignancy as they should be done in any patient. Education on modifiable risk behaviors in patients with oral cancer is the cornerstone of prevention. HPV vaccination, oral hygiene practices and annual dental screening starting from the early childhood is mandatory. 71
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Oral lesions can be easily observed by direct visualization, however, proper training and knowledge of the differential diagnosis of oral lesions is mandatory for early diagnosis of malignant and pre-malignant lesions in the oral cavity. In selected cases image analysis of tongue smears is important. Finally,
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standardized surveillance policies have to be implemented in high-risk groups.72
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Conclusions
Oral cancerous and pre-cancerous lesions have been reported in patients with IBD as they have already been reported for years now in other groups of
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immunosupressed or transplanted patients. By retrieving the existing literature it became evident that patients with IBD belong to the high-risk group of developing
M
these lesions, a phenomenon strengthened also by the increasing HPV prevalence. Currently no special precautions have been implemented to modify
ed
this risk and there are no standard approaches or guidelines for the optimal screening and disease management in such complex cases. We need
pt
prospective studies to assess the prevalence, risk and prognosis of oral Ca in
ce
well-defined IBD patient groups. It would be of importance to implement strategies for better physician and patient
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awareness regarding this important topic also in the view of the new and evolving therapies for inflammatory bowel diseases.
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ACKNOWLEDGMENT All authors have made substantial contributions to all of the following: -Conception and design of the review.
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-Final approval of the version to be submitted.
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-Drafting the article and revising it critically for important intellectual content.
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Oral lesions can be easily observed by direct visualization, however, proper training and knowledge of the differential diagnosis of oral lesions is mandatory for early diagnosis of malignant and pre-malignant lesions in the oral cavity. In selected cases image analysis of tongue smears is important. Finally,
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standardized surveillance policies have to be implemented in high-risk groups.72
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Conclusions
Oral cancerous and pre-cancerous lesions have been reported in patients with IBD as they have already been reported for years now in other groups of
an
immunosupressed or transplanted patients. By retrieving the existing literature it became evident that patients with IBD belong to the high-risk group of developing
M
these lesions, a phenomenon strengthened also by the increasing HPV prevalence. Currently no special precautions have been implemented to modify
ed
this risk and there are no standard approaches or guidelines for the optimal screening and disease management in such complex cases. We need
pt
prospective studies to assess the prevalence, risk and prognosis of oral Ca in
ce
well-defined IBD patient groups. It would be of importance to implement strategies for better physician and patient
Ac
awareness regarding this important topic also in the view of the new and evolving therapies for inflammatory bowel diseases.
Manuscript Doi : 10.1093/ecco-jcc/jjv122
hematopoietic stem cell transplant recipients. Support Care Cancer. 2012;20:3231-40. 9. King GN, Healy CM, Glover MT, Kwan JT, Williams DM, Leigh IM, Worthington HV, Thornhill MH. Increased prevalence of dysplastic and
1995;332:1052-7.
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malignant lip lesions in renal-transplant recipients. N Engl J Med.
10. Saigal S, Norris S, Muiesan P, Rela M, Heaton N, O'Grady J. Evidence of risk
for
post
transplantation
malignancy
based
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differential
on
pretransplantation cause in patients undergoing liver transplantation. Liver
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Transpl. 2002;8:482-7.
11. Di Stasio D, Guida A, Salerno C, Contaldo M, Esposito V, Laino L,
(Elite Ed). 2014;6:370-6.
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Serpico R,Lucchese A. Oral lichen planus: a narrative review. Front Biosci
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12. Dunsche A, Härle F. Precancer stages of the oral mucosa: a review. Laryngorhinootologie. 2000;79:423-7.
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13. Gillenwater AM, Vigneswaran N, Fatani H, Saintigny P, El-Naggar AK. Proliferative verrucous leukoplakia (PVL): a review of an elusive pathologic
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entity! Adv Anat Pathol. 2013;20:416-23. 14. Rushing EC, Hoschar AP, McDonnell JK, Billings SD. Iatrogenic oral hairy
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leukoplakia: report of two cases. J Cutan Pathol. 2011;38:275-9. 15. Itin P. Oral hairy leukoplakia in HIV-negative immunosuppressed patients. J Am Acad Dermatol. 1990;23:957-8.: 16. Wilczyńska-Borawska M, Małyszko J, Stokowska W. Oral cavity changes in patients after kidney transplantation and preventive-treatment algorithms. Przegl Lek. 2010;67:1322-4.
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17. Piselli P, Verdirosi D, Cimaglia C, Busnach G, Fratino L, Ettorre GM, De Paoli P, Citterio F, Serraino D. Epidemiology of de novo malignancies after solid-organ transplantation: immunosuppression, infection and other risk factors. Best Pract Res Clin Obstet Gynaecol. 2014;28:1251-65
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18. Rinaldi M, Pellegrini C, D'Armini AM, Aiello M, Negri M, Arbustini E, Ippoliti G, Viganò M. Neoplastic disease after heart transplantation: single center experience. Eur J Cardiothorac Surg. 2001;19:696-701.
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19. Rosa-Garc Iacute A E, Mondrag Oacute N-Padilla A. Oral lesions associated to immunosuppression in kidney transplant patients. Rev Med Inst
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Sica G, Rizzello F, Mocciaro F, Onali S, Calabrese E, Cottone M, Pallone F.
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Cancer in
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43. Cottone M, Kohn A, Daperno M, Armuzzi A, Guidi L, D'Inca R, Bossa F,
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44. Colombel JF, Sandborn WJ, Panaccione R, Robinson AM, Lau W, Li J, Cardoso AT.
Adalimumab safety in global clinical trials of patients with
Crohn's disease. Inflamm Bowel Dis. 2009;15:1308-19. 45. Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D'Haens G, Wolf DC, et al. Adalimumab induces and maintains clinical remission in patients
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with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:25765.e1-3. 46. Fidder H, Schnitzler F, Ferrante M, Noman M, Katsanos K, Segaert S, Henckaerts L, Van Assche G, Vermeire S, Rutgeerts P. Long-term safety of
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47. Katsanos KH, Tatsioni A, Pedersen N, Shuhaibar M, Ramirez VH, Politi
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P,Rombrechts E, Pierik M, Clofent J, Beltrami M, Bodini P, Freitas J, Mouzas I,Fornaciari G, Moum B, Lakatos PL, Vermeire S, Langholz E, Odes S, Morain
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48. Katsanos K, Ferrante M, Fidder H, Henckaerts L, Christodoulou D, Van Assche G, Tsianos E, Vermeire S, Rutgeerts P. Long-term safety of
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azathioprine treatment in inflammatory bowel disease: results from a single referral center.. J Crohns Colitis 2007;1:2 (P095)
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49.Fraser AG, Orchard TR, Robinson EM, Jewell DP. Long-term risk of
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malignancy after treatment of inflammatory bowel disease with azathioprine. AlimentPharmacol Ther. 2002;16:1225-32.
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50. Nyboe Andersen N, Pasternak B, Basit S, Andersson M, Svanström H, Caspersen S, Munkholm P, Hviid A, Jess T. Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA. 2014 Jun 18;311(23):2406-13. 51. Chao TJ. Adalimumab in the management of cutaneous and oral lichen planus. Cutis. 2009;84:325-8.
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52. Worsnop F, Wee J, Natkunarajah J, Moosa Y, Marsden R. Reaction to biological drugs: infliximab for the treatment of toxic epidermal necrolysis subsequently
triggering
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53. Moss AC, Treister NS, Marsee DK, Cheifetz AS. Clinical challenges and images in GI. Oral lichenoid reaction in a patient withCrohn's disease receiving infliximab. Gastroenterology. 2007;132:488.
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54. Mocciaro F, Orlando A, Renna S, Rizzuto MR, Cottone M. Oral lichen planus after certolizumab pegol treatment in a patient with Crohn's disease. J
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55. Flückiger R, Laifer G, Itin P, Meyer B, Lang C. Oral hairy leukoplakia in a patient with ulcerative colitis. Gastroenterology. 1994 Feb;106(2):506-8.
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56. Ben Slama L. Precancerous lesions of the buccal mucosa. Rev Stomatol Chir Maxillofac. 2001;102:77-108.
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57. Beaugerie L, Sokol H, Seksik P. Noncolorectal malignancies in
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58. Pedersen EG, Pottegård A, Hallas J, Friis S, Hansen K, Jensen PE, Gaist D. Use of azathioprine for non-thymoma myasthenia and risk of cancer: a
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nationwide case-control study in Denmark. Eur J Neurol. 2013;20:942-8. 59. Armstrong RG, West J, Card TR. Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study. Am J Gastroenterol. 2010;105:1604-9.
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60. Li AC, Warnakulasuriya S, Thompson RP. Neoplasia of the tongue in a patient with Crohn's disease treated with azathioprine: case report. Eur J Gastroenterol Hepatol. 2003;15:185-7. 61. Vilas-Boas F, Magro F, Balhau R, Lopes JM, Beça F, Eloy C, Lopes S,
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Macedo G. Oral squamous cell carcinoma in a Crohn's disease patient taking
azathioprine: case report and review of the literature. J Crohns Colitis. 2012;6:792-5.
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62. Pasternak B, Svanström H, Schmiegelow K, Jess T, Hviid A. Use of
azathioprine and the risk of cancer in inflammatory bowel disease. Am J
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Epidemiol. 2013 1;177:1296-305.
63. Beaugerie L, Carrat F, Colombel JF, Bouvier AM, Sokol H, Babouri A, F, Laharie D, Faucheron JL, Simon T, de Gramont A, Peyrin-
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Carbonnel
Biroulet L; CESAME Study Group. Risk of new or recurrent cancer under
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immunosuppressive therapy in patients with IBD and previous cancer. Gut. 2014;63:1416-23
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64. Rousseau A, Taberne R, Siberchicot F, Fricain JC, Zwetyenga N. Cancer of the cheek in a patient under etanercept. Rev Stomatol Chir Maxillofac.
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2009;110:306-8.
65. Antoniou C, Dessinioti C, Vergou T, Stratigos AJ, Avgerinou G, Kostaki
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M,Katsambas A. Sequential treatment with biologics: switching from efalizumab to etanercept in 35 patients with high-need psoriasis. J Eur Acad Dermatol Venereol. 2010;24:1413-20. 66. Rouxel AM, Le Toux G, Misery L. Tacrolimus mouthwash as second-line treatment
for
2010;137:648-9.
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67.
Kuijken
I,
Bavinck
JN.
Skin
cancer
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immunosuppressive therapy in organ transplant recipients: epidemiology and proposed mechanisms. BioDrugs. 2000;14:319-29. 68.Torres J, Buche S, Delaporte E, Colombel JF. Skin side effects of
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inflammatory bowel disease therapy. Inflamm Bowel Dis. 2013;19:1086-98.
69.Bernheim O, Colombel JF, Ullman TA, Laharie D, Beaugerie L, Itzkowitz
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SH. The management of immunosuppression in patients with inflammatory bowel disease and cancer. Gut. 2013;62:1523-8.
70. Beaugerie L. Use of immunosuppressants and biologicals in patients with
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ME,Bustamante-Ramírez MA. Oral lesions in a group of kidney transplant patients. Med Oral Patol Oral Cir Bucal. 2005;10:196-204.
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72. Komitowski DD, Helfrich SI, Schmitt BA, Freese KU. Subclinical human immunodeficiency virus-related changes in oral mucosa shown by image
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analysis of tongue smears. Am J Clin Pathol. 1993;100:433-8
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TABLES Table 1. Oral cancers reported in patients with inflammatory bowel disease. Table 2. Oral precancerous lesions reported in patients with inflammatory
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bowel disease.
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FIGURE LEGENDS Important notice: All figures illustrate original cases of non-IBD non-HIV patients and all are courtesy of Professor Emmanuel Delaporte (ED) and/or
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Dr Aledandre Brygo (AB) Figure 1. The puzzle of mechanisms and conditions leading to the
development of oral precancerous lesions and oral cancer in inflammatory
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bowel diseases.
Figure 2. Different types of oral lichen planus (OLP) in non-IBD non-HIV
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patients.
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a. Typical oral lichen planus (OLP) of the tongue’s right side. (AB) b. Diffuse OLP, plaque form, of the entire oral mucosa. Note the
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leukokeratotic aspect to be distinguished from a leukokeratosis. (AB)
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c. Cheek’s OL erosive and planus. (AB & ED) d. Tongue’s atrophic OLP after a long time evolution. Note the typical network
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of overlapping white striae of the point. (AB)
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Figure 3. Oral squamous cell carcinoma in non-IBD non-HIV patients. a.Squamous cell carcinoma (SCC) of the tongue’s point arising on an atrophic oral lichen planus. (ED) b.SCC of the tongue in a 19-year-old smoker female. The question of the responsability of HPV as cofactors is raised in such a case. (AB & ED)
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c.Typical SCC of the lower lip in a smoker patient arising on a leukokeratosis. (ED) d.SCC of the lower lip in a young male, rapidly appeared after a kidney
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transplantation. (ED) Figure 4. Melanoma of the soft palate in non-IBD non-HIV patient.( ED)
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Figure 5. Kaposi sarcoma of the hard palate in non-IBD non-HIV patient.(ED)
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Table 1. Oral cancers reported in patients with inflammatory bowel disease. Patient(s) with oral Ca
Disease
Location / Type of oral cancer
Details
1
CD
Surgery
AZA (3 years) IFX+AZA
1
CD
1
IBD
non-biological therapies IFX or Any other therapy
1
CD
6
CD
Right superior retromollar trigone, SCC / HPV (-) Tongue SCC (ulcerous in situ) Parotid Non-Hodgkin lymphoma Oropharyngeal (larynx) Oral cavity (3 patients on IFX)
Cottone et al. (cohort study) 62 Pasternak et al. (Danish IBD cohort database n=45,986)
IFX=2,475 ADA=604 AZA= 5,197
1 0 69
CD
Nyboe- Andersen et 50 al. (Danish IBD cohort database)
antiTNF=4,553 non -antiTNF =51,593
AZA (9 years)
60
Li et al. (case report) 39 Dulai et al. (case report) 26
Biancone et al. (multicenter study) 42 Lichtenstein et al. (TREAT cohort registry n=6,773)
45
Oral cavity SCC
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CD
47
Katsanos et al. (EC-IBD cohort n=681)
48
Katsanos et al. (Leuven cohort
Unknown Death
SIR (95%(CI) IFX-treated 1.77 (0.37, 5.17) Any other therapy 1.78 (0.37, 5.21) 18 months after IFX (died) RR 95%(CI) Non-users (referrent) Former users 1.70 (0.63-4.60) Users 1.69 (0.57-5.00) Crude 1.24 (0.39-3.93) Adjusted 1.47 (0.43-5.00) Adjusted for use of azathioprine 1.08 (0.31-3.70) 1 of total 35 Ca on ADA 40, males, African-American (oral cavity cancer), fair skin (lip cancer)
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DNA detected from CMV and EBV in oral cancerous lesions, chronic candidiasis) Education level
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(Absence of oral screening, no annual oral exam, poor oral hygiene) Nutrition deficiencies
(low vitamin A, B12, folic acid levels, iron deficiency)
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(traumatic ulcers, poor fitting denture, broken or sharp-edged teeth or fillings)
Drugs
(immunosuppressants,
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Infections (HPV E6 and E7 oncogenes, HIV, syphilis
Chronic irritation in oral cavity
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Life style (smoking , smokeless tobacco use, pipe smoking, marijuana use, heavy alcohol use, access to medical care or dental care, low consumption of fruits and vegetables)
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Environmental factors
anti-TNFa ?, others?)
Underlying conditions (immunodeficiency, transplantation, Plummer-Vinson)
Alterations in oral homeostasis (xerostomia, reduced salivary flow, candida colonization)
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Precancerous oral lesions unrecognized and untreated
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(leukoplakia, erythroplakia, leukoerythroplakia, chronic candidiasis (?) p53 gene alterations-dysplasia-cancer in situ-invasive cancer
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REVIEW "Oral cancer and oral precancerous lesions in inflammatory bowel
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diseases, a systematic review”
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Short running title: Oral cancer and IBD
Konstantinos H. Katsanos1, Giulia Roda1, Alexandre Brygo2, Emmanuel
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Delaporte3, Jean-Frédéric Colombel1.
1
The Leona M. Harry B. Helmsley Inflammatory Bowel Disease Center, The
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Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at
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Mount Sinai, One Gustave Levy Place, New York, 10029 NY, USA. 2
Department of Stomatology, Centre Hospitalier Régional Universitaire de
3
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Lille 2, avenue Oscar Lambret - 59037 Lille Cedex, France. Department of Dermatology, Centre Hospitalier Régional Universitaire de
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Lille 2, avenue Oscar Lambret - 59037 Lille Cedex, France.
Abbreviations used in the text: IBD: inflammatory bowel disease, CD: Crohn’s disease, UC: ulcerative colitis, anti-TNFa: antibody to tumor necrosis factor alpha, IS: immunosuppressant(s) Conflict of interest and funding: None
Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
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Author responsible for correspondence and reprints: Jean-Frédéric Colombel, MD
The Henry D. Janowitz Division of Gastroenterology Icahn School of Medicine at Mount Sinai
Phone:(212)241-4299, Fax: (212) 426-5099
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e-mail: [email protected]
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One Gustave Levy Place, New York, 10029 NY, USA.
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The Leona M. and Harry B. Helmsley Inflammatory Bowel Disease Center
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Abstract Oral cancer is historically linked to well-known behavioral risk factors such as tobacco smoking and alcohol consumption. Other risk factors include age over forty, male sex, several dietary factors, nutrition deficiencies, viruses,
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sexually transmitted infections, human papillomavirus, chronic irritation and possibly genetic predisposition. Precancerous lesions in the oral cavity
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include leukoplakia, erythroplakia and lichen planus. Histology of oral cancer varies largely but the great majority is squamous cell carcinomas.
Epidemiological studies and cancer registries have shown a consistently
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increased risk of oral malignancies in kidney, bone marrow, heart or liver transplantation, in graft versus host disease and in patients with HIV infection.
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Because of the increasing use of immunosuppressive drugs in patients with inflammatory bowel disease it is useful to more accurately delineate the
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consequences of chronic immunosuppression to the oral cavity. Oral cancer and pre-cancerous oral lesions in patients with IBD have been scarcely
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reported and reviews on the topic are lacking. We conducted a literature search using the terms and variants of all
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cancerous and precancerous oral manifestations of inflammatory bowel diseases. By retrieving the existing literature it is evident that patients with
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IBD belong to the high-risk group of developing these lesions, a phenomenon strengthened also by the increasing HPV prevalence. Education on modifiable risk behaviors in patients with oral cancer is the cornerstone of prevention. Oral screening should be performed for all IBD patients, especially those who are about to start a immunosuppressant or a biologic.
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Key words: Inflammatory bowel disease, Crohn's disease, ulcerative colitis, oral cancer, oral malignancy, oral precancerous lesions, immunosuppressant,
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azathioprine, biological therapies, anti-TNFa.
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INTRODUCTION Epidemiological studies and cancer registries have shown a consistently increased risk of head and neck malignancies in patients undergoing kidney, bone marrow, heart or liver transplantation, in graft versus host disease and in
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patients with HIV infection although the calculated risk differs markedly between studies essentially because of differences in methodologies and selection of
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patients. Skin, lip, buccal cavity and tongue cancers, lymphomas, melanomas and Kaposi's sarcomas, are the main types of cancer reported in these patients.1 Oral cancer is historically linked to well-known behavioral risk factors such as
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tobacco smoking and alcohol consumption. Other main risk factors are age over 40 and male sex.2 In addition, several dietary factors, nutrition deficiencies,
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viruses, sexually transmitted infections, chronic irritation and possibly genetic predisposition have been also associated with oral cancer.3
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Substantial evidence has been mounting that human papillomavirus (HPV) infection is playing an increasing important role in oral cancer. In fact, HPV
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infection is recognized as one of the major causes of infection-related cancer worldwide. Indeed, strong evidence for a causal etiology with HPV has been
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stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx including base of the
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tongue and tonsils. Of the estimated new cancers occurring each year worldwide, 4.8% are attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries.4 Extra-intestinal malignancies in inflammatory bowel disease (IBD) have been linked with various aetiologies except of the disease itself. Oral cancer and pre-
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cancerous oral lesions in patients with IBD have been scarcely reported and reviews assessing the magnitude of this problem are lacking. Herein, we review systematically all data on epidemiology, aetiopathogenesis, and risk factors of oral malignant and pre-malignant lesions and conditions
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associated with IBD, and we provide a comprehensive guide for clinicians regarding the principles of optimal therapeutic management of these challenging
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extra-intestinal malignancies in patients with IBD.
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SEARCH STRATEGY
A comprehensive literature search using the terms and variants of all
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cancerous and precancerous oral manifestations of inflammatory bowel diseases (ulcerative colitis, Crohn’s disease) was performed in January 2015
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within Pubmed, Embase and Scopus and was restricted to human studies (1946 to 2015, January) and EMBASE (1947 to January, 2015). Studies were included if they were published in any language and if related to oral
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malignant or pre-malignant lesions or conditions with special focus on IBD.
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Additionally, references from relevant literature were hand searched (search
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strategy is available in the Appendix).
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EPIDEMIOLOGY AND PATHOGENESIS OF ORAL CANCER
The term oral cancer refers to cancers of the mucosal surfaces of the lips, floor of mouth, tongue, buccal mucosa, lower and upper gingival, hard palate and
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retromolar trigone.5 Head and neck cancer represent the sixth most common malignancy worldwide while the annual incidence of oral cancer exceeds 3,000,000 new cases.
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Several aetiopathogenetic mechanisms have been suggested so far [Figure 1]
but the pathogenesis of oral cancer still needs further elucidation. There are several reports on mucosal immunodeficiency in smokers and on changes of the
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saliva in patients under immunosuppressive or anti-neoplastic therapy.6 Reduced saliva volume and change in saliva constituents may affect epithelial
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maintenance and repair, the physiology of the oral microflora, and the interaction between the oral flora and the epithelium.7 Chronic oral candidiasis has been
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also suggested as a potential pathogenetic mechanism especially in patients with
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prolonged steroid use.8
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RISK FACTORS OF ORAL CANCER
Risk factors for oral cancer can be divided into precancerous lesions and precancerous states such as conditions related to life style (i.e smoking, alcohol consumption), to medical therapy or to carriage of oncogenic viruses.
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a. Precancerous lesions Diagnosis of oral cancerous lesions is generally easy but early recognition of precancerous lesions and precancerous conditions is often challenging, especially in patients that belong to high risk groups. It is important to
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underline here that most oral cancers do not develop from pre-existing precancerous lesions.
Precancerous lesions include chronic lesions of the oral cavity on which
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cancer of the oral cavity is known to develop with low to high probability. 9 These include: leucoplakia, oral lichen planus, erythroplakia, papillomatous lesions, actinic cheilitis, submucosal fibrosis, keratotic candidosis, and tertiary
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syphilis. The precancerous states include cancers occasionally observed in the oral cavity during any kind of immunosuppression or other conditions
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related to therapy and to lifestyle.10
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Oral lichen planus
Oral lichen planus is a common disease of unknown aetiology affecting oral
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mucosae. It is characterized by T-cell mediated chronic inflammation and has
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been clinically associated with development of oral squamous cell carcinoma although the risk for neoplastic change seems low [Figure 2].11
Malignant
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transformation is seen in less than 2% of the patients within 10 to 15 years. 12 Histologically the oral lichen planus does not differ from the oral lichenoid reactions which are lesions mostly found in contact with amalgam restorations. In such cases a causative treatment with replacement of the amalgam is recommended. Leukoplakia, erythroplakia and erythroleukoplakia
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The most frequent causes of leukoplakia and erythroplakia are smoking, chewing tobacco and poorly fitting dentures. Most cases of leukoplakia do not develop into cancer but some leukoplakias are either cancerous when first found or have precancerous changes. Erythroplakia and erythroleukoplakia are less common but
rip t
are usually more serious.13
Oral hairy leukoplakia has been suggested as a marker for severe immunosuppression and was initially described in immunocompromised men
us c
infected with the human immunodeficiency virus (HIV)14 but has also been
described in other iatrogenic instances such as in immunocompromised 15, and
an
transplanted16 patients.
M
b. Precancerous states The role of immunosupression
ed
Immunosuppressive drugs seem to substantially contribute to skin/lip and oral cancer development after organ transplantation, either as a result of
pt
immunosuppression or through specific carcinogenic mechanisms [Appendix
ce
Table 1]. Prolonged immunosuppression for multiorgan chronic graft-versus-host disease
increases
the
risk
of
oral
cancer17
while
double
or
of
Ac
immunosuppression also increases this risk.18 In addition, the extent
triple
immunosuppression as expressed by lower total leukocyte count was related to an increased risk of hairy leukoplakia in kidney transplant patients.19 Thiopurines Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) may promote cancers by various mechanisms including carcinogenic mutations of cell DNA,
Manuscript Doi : 10.1093/ecco-jcc/jjv122
impaired immunosurveillance of tumour cells, impaired number or function of immune cells chronically infected by Epstein-Barr Virus (EBV) or HPV and several others. Methotrexate
rip t
In general, the use of MTX monotherapy or in combination with other
immunosuppressants has been reported to be safe in rheumatology20 or in
us c
patients with psoriasis.21 Of note, MTX has been used as anti-neoplastic therapy for head-neck cancers and for oral florid papillomatosis.22 Corticosteroids
an
A single study suggested that the use of oral glucocorticoids may increase the risk of skin cancers and in particular, among patients other than organ transplant
Biological therapies
M
recipients, but this has to be further confirmed.23
ed
Tumour necrosis factor-alpha is a cytokine produced by activated T cells and macrophages determining in vitro a necrotizing effect on tumor cells. Blocking
pt
TNF-alpha has therefore been hypothesized to increase the overall cancer risk.
ce
Rare cases of oral cancer or precancerous lesions on anti-TNFa and biological therapies have been reported in non-IBD patients [Appendix Table 2] including
Ac
also one case of oral candidiasis in a patient with sarcoidosis on infliximab. 24 Another study on the influence of TNF-α blockers on the oral prevalence of opportunistic microorganisms in patients with ankylosing spondylitis showed that anti-TNF-α therapy could not be correlated with increased counts of microorganisms.25
Manuscript Doi : 10.1093/ecco-jcc/jjv122
Studies including patients with rheumatoid arthritis on anti-TNFa therapies did not find any evidence for an excess cancer risk on TNF-α antagonists but according to the authors an excess cancer risk after several years of exposure cannot be ruled out.26
rip t
The past few years have seen an increased interest in the implications of integrin
receptors in cancer biology and tumor cell aggression. No case of oral cancer
during anti-integrin therapy has been so far reported. Long-term risk assessment
us c
of oral cancer in patients on biological requires observational studies and safety-
Oncogenic viruses Human papillomavirus (HPV)
an
assessments using randomized controlled trials meta-analyses.
M
A rise in incidence of oropharyngeal squamous cell cancer in non-transplanted white men younger than 50 years who have no history of alcohol or tobacco use
ed
has been recorded over the past decade and this was associated with human papillomavirus (HPV) 16 infection. Of interest, the biology of HPV-positive
pt
oropharyngeal cancer is distinct with P53 degradation, retinoblastoma RB
ce
pathway inactivation, and P16 up regulation. By contrast, tobacco-related oropharyngeal cancer is characterized by TP53 mutation.27 Sometimes the term
Ac
«oropharynx» introduces a confusion as, according to some physicians, it is meant to include
also the buccal cavity. In fact, the oropharynx includes
everything that lies behind the tonsils. So, from one hand it is right to support that oropharyngeal cancers are linked to HPV, by the other hand in the buccal cavity, the role of HPV is debatable. Thus, a clear separation for the role of HPV
Manuscript Doi : 10.1093/ecco-jcc/jjv122
regarding carcinogenesis in the buccal cavity and the oropharynx has to be evaluated. Epstein-Barr virus (EBV) Epstein-Barr virus (EBV) is classically associated with Burkitt's lymphoma, B-cell
rip t
lymphoproliferative syndromes, nasopharyngeal carcinoma, Hodgkin's disease, T-cell lymphomas, thymic lymphoepithelial carcinoma, gastric carcinoma and oral
hairy leukoplakia.28 EBV presence and oral manifestations have been also
us c
reported in patients who had undergone bone marrow transplantation 29 and heart
an
transplantation.30
TAXONOMY OF ORAL CANCEROUS LESIONS
M
Taxonomy of oral cancerous lesions includes location, histology and HPV
ed
positivity. Taxonomy by location Lip cancer
pt
A case of squamous cell carcinoma of the lip associated with adalimumab
ce
therapy for ankylosing spondylitis31 has been reported so far. Although the increased risk of non melanoma skin cancer including dysplastic and malignant
Ac
lip lesions in immunosuppressed solid organ transplant patients is well known 32, the association with inflammatory bowel disease remains unknown. Buccal cancer Among the most common malignancies observed in transplant recipients were non melanomatous skin cancers and squamous cell cancers of the buccal cavity.33
Manuscript Doi : 10.1093/ecco-jcc/jjv122
Gingival cancer Gingival cancer can be primary or metastatic. The most common primary sources of metastatic tumours to the oral region are the breast, lung, kidney, bone, colon while choriocarcinoma and hepatocellular carcinoma metastatic to the maxillary
rip t
gingival may also occur.34-35 Tongue cancer
us c
In transplant recipients, erythroplakia of the tongue36, lymphoproliferative disease37 and squamous cell tongue carcinoma have been described.38
an
Taxonomy by histology and HPV positivity
Histology of oral cancer varies largely but more than 9 of 10 cancers of the
M
oral cavity and oropharynx are squamous cell carcinomas [Figure 3]. There are also other types including non-squamous, lymphoma, melanoma [Figure
ed
4], non-melanoma, metastatic and other rare types such as Kaposi sarcomas [Figure 5].39 Finally, characterization of oral cancers by HPV positivity is
pt
important for disease diagnosis and prognosis.
ce
ORAL CANCER PROGNOSIS Prognosis of oral cancer differs significantly among specific oral locations, with
Ac
cancer of the lip, for example, having a much better prognosis compared to a cancer at the base of tongue or on the gingiva. 3 Prognosis of intra-oral cancer is generally poor, with a five-year survival less than 50 percent. Especially in post transplant oral tumors outcomes are worse compared to the normal population. Local recurrences occur in a significant percentage of patients, while distant metastases are less frequent. Prognosis correlates mainly with the size of the
Manuscript Doi : 10.1093/ecco-jcc/jjv122
lesion and the nodal status at the time of diagnosis.40 Of importance, HPV positivity is correlated with better cancer outcomes. A significant association of p16 (INK4a) overexpression with improved survival in young patients with squamous cell cancers of the oral tongue has also been demonstrated. However,
us c
EPIDEMIOLOGY OF ORAL CANCER IN IBD
rip t
p16 (INK4a) overexpression was not a reliable predictor of HPV positivity.41
The incidence and prevalence of oral cancerous and pre-cancerous lesions in IBD is currently unknown. It could also be possible that oral cancers in IBD
an
were grouped together in the past within the upper digestive track cancers or head and neck cancers group, thus overshadowing the exact magnitude of
M
the problem. Moreover, no routine oral screening for IBD patients, especially for those who are about to start an immunosuppressant or a biological therapy
ed
is performed or is advised so far.
Direct or indirect information for the occurrence of oral malignancies in IBD
pt
were extracted -with every possible caution and after meticulous search and analysis- from large cohort studies, clinical trials and rare case reports [Table
ce
1]. According to this data the prevalence of oral cancer in IBD seems probably to be low as the risk for oral cancer in IBD has been estimated to range from
Ac
1.08 (0.31-3.70) to 1.78 (0.37, 5.21).42-50 Taking into account all above limitations in the oral cancer risk calculations, it
is evident that well-designed prospective studies are urgently needed to clearly assess the real magnitude of the risk of oral cancer in IBD and to possibly identify high-risk groups of patients needing close surveillance.
Manuscript Doi : 10.1093/ecco-jcc/jjv122
RISK FACTORS OF ORAL CANCER IN IBD
a. Precancerous lesions
rip t
Although the prevalence of these lesions has been reported to be significantly increased in transplant recipients, they have been rarely reported in patients with
IBD [Table 2]. Successful adalimumab use for oral lichen planus has been
us c
reported51 and there are also reports on paradoxical triggering of erosive lichen
planus during infliximab treatment52-53 and of de novo oral lichen planus occurence after certolizumab pegol treatment in a patient with Crohn's disease. 54
an
Oral hairy leukoplakia has been once reported in a patient with ulcerative
ed
precancerous states.56
M
colitis.55 Of note, precancerous lesions have to be distinguished from
b. Treatment-related risk factors
pt
IBD patients receiving immunosuppressive therapy are theoretically at an increased risk of developing extraintestinal malignancies.57-59 However, the exact
ce
magnitude of this risk is currently unknown as it may occur in cancers where
Ac
absolute numbers may be low but relative risk may be high. Thiopurines So far, two cases of oral cancer during azathioprine (AZA) therapy have been reported in IBD, both in patients with Crohn’s disease. The first was a case of a 39-year-old non-smoking male with Crohn's disease who had been treated for 3 years with azathioprine and developed a lingual ulcer. Biopsy revealed
Manuscript Doi : 10.1093/ecco-jcc/jjv122
squamous cell carcinoma of the tongue.60 The second one was a case of a 33year-old Caucasian woman with Crohn's disease treated with azathioprine for 9 years who developed an ulcerated lesion at the right superior retromolar trigone and in which subsequent biopsy revealed a squamous cell carcinoma. 61
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In general, in patients with IBD, azathioprine use was associated with an increased risk of overall cancer (rate ratio = 1.41, 95% confidence interval: 1.15, 1.74), whereas former use of azathioprine (rate ratio = 1.02, 95% confidence
us c
interval: 0.83, 1.25) or increasing cumulative received doses were not. 62 Patients with IBD with a history of cancer are at increased risk of developing any new or recurrent cancer, with a predominant incidence of new cancers. Treatment with
an
immunosuppressants has no overall major impact per se on this risk. 63
It should be emphasized that, the doses of immunosuppression used in
M
transplanted patients are significantly higher than those used in IBD, so it is
Methotrexate
ed
difficult to suggest a parallel degree of risk.
pt
No cases of oral cancer during methotrexate (MTX) therapy for IBD has been reported so far. In addition, there is no study in the literature supporting an
ce
excess risk of cancer in IBD patients who are exposed to methotrexate. Calcineurin inhibitors
Ac
Cyclosporin A and tacrolimus are used in a minority of patients with IBD and most of the time on a short-term basis. No safety data are available on the risks of cancer associated with the use of these drugs in IBD and no case of oral cancer has been so far reported during or after the use of these two drugs. Corticosteroids There is no report on oral cancer under corticosteroid use in IBD patients so far.
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Biological therapies Several studies have investigated the cancer risk associated with anti-TNFs use in IBD but none of them has focused on oral cancer risk. One limitation of these studies is that most of the IBD patients treated with anti-TNFs have either a
rip t
concurrent or a past use of thiopurines, thus making difficult to evaluate the cancer risk related to anti-TNFs alone. Current evidence suggests that the use of anti-TNFs alone in IBD is not associated with a significant increase in the overall
us c
cancer risk. There are also scarce reports on oral cancer during biological
therapy in other autoimmune-based diseases.64-65 No case of oral cancer during
an
anti-integrin therapy in IBD has been reported so far.
M
TREATMENT OF ORAL CANCER IN IBD PATIENTS Conventional treatment of oral cancer
ed
Conventional treatment approaches of oral cancer include surgery, radiotherapy and adjuvant systemic chemotherapy. Various combinations of these approaches
pt
may be selected depending on the disease presentation and pathological findings. Treatment of oral precancerous lesions includes surgical excision or/and
ce
topical application of calcineurin inhibitors but therapy has to be individualized. 66
Ac
Modification of immunosuppression Management of immunosuppression in patients with IBD diagnosed also with oral cancer
or
precancerous
lesions
is
challenging.
Modification
of
immunosuppression has been proved to be important in those patients but the detailed principles of management of immunosuppression after cancer diagnosis are debatable.
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Changing the immunosuppressive regimen from azathioprine to cyclosporin or vice versa does not seem to relieve skin predisposition to cancer.67 Apart from immunosuppressive therapy modifications, exposure to sunlight and infection with human papillomaviruses as well as oral screening for preexistent occult
Special oncologic issues and prevention of recurrence
rip t
carcinomas are believed to represent the most important preventive measures.
us c
Primary or metastatic tumours to the oral region have to be always excluded
before starting immunomodulators or biological therapies in IBD patients. In
has to be set on individual basis.
an
cases with documented oral precancerous lesions the prioritization of treatment
Oral surveillance strategies in patients exposed to immunosuppressants and
M
biological is mandatory before initiation and during any therapy. Annual examination by dermatologist, stomatologist and ENT/oncologist specialist is
ed
mandatory in those patients. Based on the examination of specialists, risk assessment according to the individual risk factors (i.e smoking, precancerous
pt
lesions) and tailored case by case surveillance strategy defined for each patient
ce
will be performed.68
Management decisions regarding immunosuppression in IBD patients with a
Ac
cancer are best made in a multidisciplinary fashion and on a case by case basis, taking into account the natural history of the cancer (organ of origin, stage, histological type and prognosis). This should include the opinion of the oncologist, the time from completion of cancer treatment, the severity of the IBD and the expected impact of the immunosuppressant on the previous cancer. It
Manuscript Doi : 10.1093/ecco-jcc/jjv122
seems reasonable to withhold immunosuppressants during the treatment of active oral cancer. Within 2 years after completing cancer treatment, 5- aminosalicylates, corticosteroids, antibiotics, nutritional therapy and surgery should form the
rip t
foundation of IBD treatment. However, if these treatment modalities are
ineffective in a patient with severe IBD, then immunosuppressive therapy should be considered as rescue therapy. If a tumour has an intermediate to high risk of an
interval
of
5
years
is
preferable.
In
all
us c
recurrence,
cases,
if
immunosuppressive therapy is resumed, a step-up approach should be
an
considered, starting with monotherapies.
Anti-TNF therapy is contraindicated in patients with a history of lymphoma and careful consideration should be given to initiating anti-TNF therapy in those with a
M
history of oral cancer.69 The use of anti-TNFa therapies in IBD patients with prior oral malignancy remains a challenging topic to address because, in general,
ed
patients with prior oral malignancy are not likely to be prescribed a TNF inhibitor at least on a short-term follow up.70
pt
Although there are few data regarding the impact of steroids on cancer, the
ce
general consensus is that corticosteroids are the safer option although anti-TNFs may be a useful back-up plan.
Ac
Overall, the risks associated with biologic agents should be weighed against their potential benefits in patients with previous oral malignancy as they should be done in any patient. Education on modifiable risk behaviors in patients with oral cancer is the cornerstone of prevention. HPV vaccination, oral hygiene practices and annual dental screening starting from the early childhood is mandatory. 71
Manuscript Doi : 10.1093/ecco-jcc/jjv122
Oral lesions can be easily observed by direct visualization, however, proper training and knowledge of the differential diagnosis of oral lesions is mandatory for early diagnosis of malignant and pre-malignant lesions in the oral cavity. In selected cases image analysis of tongue smears is important. Finally,
rip t
standardized surveillance policies have to be implemented in high-risk groups.72
us c
Conclusions
Oral cancerous and pre-cancerous lesions have been reported in patients with IBD as they have already been reported for years now in other groups of
an
immunosupressed or transplanted patients. By retrieving the existing literature it became evident that patients with IBD belong to the high-risk group of developing
M
these lesions, a phenomenon strengthened also by the increasing HPV prevalence. Currently no special precautions have been implemented to modify
ed
this risk and there are no standard approaches or guidelines for the optimal screening and disease management in such complex cases. We need
pt
prospective studies to assess the prevalence, risk and prognosis of oral Ca in
ce
well-defined IBD patient groups. It would be of importance to implement strategies for better physician and patient
Ac
awareness regarding this important topic also in the view of the new and evolving therapies for inflammatory bowel diseases.
Manuscript Doi : 10.1093/ecco-jcc/jjv122
ACKNOWLEDGMENT All authors have made substantial contributions to all of the following: -Conception and design of the review.
Ac
ce
pt
ed
M
an
us c
-Final approval of the version to be submitted.
rip t
-Drafting the article and revising it critically for important intellectual content.
Manuscript Doi : 10.1093/ecco-jcc/jjv122
Oral lesions can be easily observed by direct visualization, however, proper training and knowledge of the differential diagnosis of oral lesions is mandatory for early diagnosis of malignant and pre-malignant lesions in the oral cavity. In selected cases image analysis of tongue smears is important. Finally,
rip t
standardized surveillance policies have to be implemented in high-risk groups.72
us c
Conclusions
Oral cancerous and pre-cancerous lesions have been reported in patients with IBD as they have already been reported for years now in other groups of
an
immunosupressed or transplanted patients. By retrieving the existing literature it became evident that patients with IBD belong to the high-risk group of developing
M
these lesions, a phenomenon strengthened also by the increasing HPV prevalence. Currently no special precautions have been implemented to modify
ed
this risk and there are no standard approaches or guidelines for the optimal screening and disease management in such complex cases. We need
pt
prospective studies to assess the prevalence, risk and prognosis of oral Ca in
ce
well-defined IBD patient groups. It would be of importance to implement strategies for better physician and patient
Ac
awareness regarding this important topic also in the view of the new and evolving therapies for inflammatory bowel diseases.
Manuscript Doi : 10.1093/ecco-jcc/jjv122
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TABLES Table 1. Oral cancers reported in patients with inflammatory bowel disease. Table 2. Oral precancerous lesions reported in patients with inflammatory
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FIGURE LEGENDS Important notice: All figures illustrate original cases of non-IBD non-HIV patients and all are courtesy of Professor Emmanuel Delaporte (ED) and/or
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Dr Aledandre Brygo (AB) Figure 1. The puzzle of mechanisms and conditions leading to the
development of oral precancerous lesions and oral cancer in inflammatory
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bowel diseases.
Figure 2. Different types of oral lichen planus (OLP) in non-IBD non-HIV
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patients.
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a. Typical oral lichen planus (OLP) of the tongue’s right side. (AB) b. Diffuse OLP, plaque form, of the entire oral mucosa. Note the
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leukokeratotic aspect to be distinguished from a leukokeratosis. (AB)
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c. Cheek’s OL erosive and planus. (AB & ED) d. Tongue’s atrophic OLP after a long time evolution. Note the typical network
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of overlapping white striae of the point. (AB)
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Figure 3. Oral squamous cell carcinoma in non-IBD non-HIV patients. a.Squamous cell carcinoma (SCC) of the tongue’s point arising on an atrophic oral lichen planus. (ED) b.SCC of the tongue in a 19-year-old smoker female. The question of the responsability of HPV as cofactors is raised in such a case. (AB & ED)
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c.Typical SCC of the lower lip in a smoker patient arising on a leukokeratosis. (ED) d.SCC of the lower lip in a young male, rapidly appeared after a kidney
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transplantation. (ED) Figure 4. Melanoma of the soft palate in non-IBD non-HIV patient.( ED)
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Figure 5. Kaposi sarcoma of the hard palate in non-IBD non-HIV patient.(ED)
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Table 1. Oral cancers reported in patients with inflammatory bowel disease. Patient(s) with oral Ca
Disease
Location / Type of oral cancer
Details
1
CD
Surgery
AZA (3 years) IFX+AZA
1
CD
1
IBD
non-biological therapies IFX or Any other therapy
1
CD
6
CD
Right superior retromollar trigone, SCC / HPV (-) Tongue SCC (ulcerous in situ) Parotid Non-Hodgkin lymphoma Oropharyngeal (larynx) Oral cavity (3 patients on IFX)
Cottone et al. (cohort study) 62 Pasternak et al. (Danish IBD cohort database n=45,986)
IFX=2,475 ADA=604 AZA= 5,197
1 0 69
CD
Nyboe- Andersen et 50 al. (Danish IBD cohort database)
antiTNF=4,553 non -antiTNF =51,593
AZA (9 years)
60
Li et al. (case report) 39 Dulai et al. (case report) 26
Biancone et al. (multicenter study) 42 Lichtenstein et al. (TREAT cohort registry n=6,773)
45
Oral cavity SCC
ed
CD
47
Katsanos et al. (EC-IBD cohort n=681)
48
Katsanos et al. (Leuven cohort
Unknown Death
SIR (95%(CI) IFX-treated 1.77 (0.37, 5.17) Any other therapy 1.78 (0.37, 5.21) 18 months after IFX (died) RR 95%(CI) Non-users (referrent) Former users 1.70 (0.63-4.60) Users 1.69 (0.57-5.00) Crude 1.24 (0.39-3.93) Adjusted 1.47 (0.43-5.00) Adjusted for use of azathioprine 1.08 (0.31-3.70) 1 of total 35 Ca on ADA 40, males, African-American (oral cavity cancer), fair skin (lip cancer)
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DNA detected from CMV and EBV in oral cancerous lesions, chronic candidiasis) Education level
ed
(Absence of oral screening, no annual oral exam, poor oral hygiene) Nutrition deficiencies
(low vitamin A, B12, folic acid levels, iron deficiency)
pt
(traumatic ulcers, poor fitting denture, broken or sharp-edged teeth or fillings)
Drugs
(immunosuppressants,
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Infections (HPV E6 and E7 oncogenes, HIV, syphilis
Chronic irritation in oral cavity
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Life style (smoking , smokeless tobacco use, pipe smoking, marijuana use, heavy alcohol use, access to medical care or dental care, low consumption of fruits and vegetables)
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Environmental factors
anti-TNFa ?, others?)
Underlying conditions (immunodeficiency, transplantation, Plummer-Vinson)
Alterations in oral homeostasis (xerostomia, reduced salivary flow, candida colonization)
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Precancerous oral lesions unrecognized and untreated
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(leukoplakia, erythroplakia, leukoerythroplakia, chronic candidiasis (?) p53 gene alterations-dysplasia-cancer in situ-invasive cancer
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