Oral Squamous Cell Carcinoma Presenting in a Patient Receiving Adalimumab for Rheumatoid Arthritis Anna Beattie, BDentSc,* Leo F. A. Stassen, MA,y and Kumara Ekanayake, MBBCh, MS, BDS, MScz The efficacy of biologic agents in the treatment of inflammatory immune-mediated conditions has been clearly shown, but there also are numerous reports of adverse effects. Most reported adverse effects have been associated with tumor necrosis factor-a (TNF-a) inhibitors and include a possible increased risk of malignancy. There have been some reported cases of oral cancer developing in patients treated with TNF-a inhibitors. This case report describes a patient who was taking adalimumab for rheumatoid arthritis and who presented with a squamous cell carcinoma (SCC) in the mandible. Diagnosis was complicated because the clinical appearance was of a nonhealing extraction socket and the patient had a history of bisphosphonate therapy. An initial diagnosis of bisphosphonate-related osteonecrosis of the jaws was made, which delayed the commencement of appropriate treatment. This case highlights the importance of ruling out SCC in patients taking biological agents with unusual symptoms. Ó 2015 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 73:2136-2141, 2015 Biological agents are increasingly being used in the treatment of inflammatory immune-mediated conditions, including rheumatoid arthritis (RA), ankylosing spondylitis, juvenile arthritis, Crohn’s disease, and psoriasis. Numerous studies have convincingly shown the clinical efficacy of these drugs.1 In patients with RA, biological agents have been shown to be superior to standard disease-modifying antirheumatic drugs in achieving disease remission and retarding bony destruction.2 However, there have been reports of adverse events: opportunistic infections, reactivation of latent tuberculosis (TB), exacerbation of cardiac failure, cutaneous reactions, and an increased rate of malignancies.3 Biological agents work by targeting specific steps in the proinflammatory pathway. They are divided into 3 main classes: tumor necrosis factor-a (TNF-a) inhibitors, such as adalimumab; interleukin inhibitors, such as ustekinumab, which inhibits interleukin-12 and interleukin-23; and lymphocyte modulators,
which include T-lymphocyte modulators, such as alefacept, and B-lymphocyte modulators, such as rituximab.3 The most commonly used biological agents are the TNF-a inhibitors, of which there are currently 3 licensed for use: adalimumab, etanercept, and infliximab. TNF-a is a proinflammatory cytokine. It mediates many inflammatory processes, including immune cell activation and proliferation, apoptosis, and regulation of leucocyte movement and adhesion. It is crucial in driving the inflammatory process and recruiting to sites of tissue inflammation. TNF-a inhibitors bind soluble and membrane-bound TNF-a, blocking its effects on target inflammatory cells.4 Adalimumab (Humira; AbbVie, Inc, North Chicago, IL) is a humanized monoclonal antibody, infliximab (Remicade; Janssen Biotech, Titusville, NJ) is a chimeric monoclonal antibody composed of human and murine regions and etanercept (Enbrel; Amgen, Inc, Thousand Oaks, CA) is a recombinant human TNF receptor fusion protein.5
Received from the Department of Oral and Maxillofacial Surgery and
Dublin Dental University Hospital, Lincoln Place, Dublin 2, Ireland;
Oral Medicine, Dublin Dental University Hospital, Dublin, Ireland. *Registrar in Oral Surgery.
e-mail: [email protected] Received March 23 2015
yProfessor and Consultant Oral and Maxillofacial Surgeon.
Accepted May 17 2015
zAssociate Professor and Consultant Oral and Maxillofacial
Ó 2015 American Association of Oral and Maxillofacial Surgeons
Surgeon.
0278-2391/15/00606-0
Address correspondence and reprint requests to Ms Beattie:
http://dx.doi.org/10.1016/j.joms.2015.05.022
Department of Oral and Maxillofacial Surgery and Oral Medicine,
2136
BEATTIE, STASSEN, AND EKANAYAKE
2137
Reports of Adverse Events
who was taking adalimumab, was found to have carcinoma in situ in the right buccal mucosa. Neither patient had any other known risk factors for SCC.17 Leao et al18 reported the case of a 39-year-old woman who had been taking adalimumab and who presented with a white patch on the lateral border of the tongue, which histology confirmed to be severe dysplasia. There was an absence of any other risk factors for dysplasia. Chainani-Wu et al19 reported on a 45-year-old man who had been taking etanercept for 5 months for RA and presented with a poorly differentiated T2N2bM0 SCC of the left tonsil. It should be noted that the patient was a smoker and that the tumor was positive for p16 immunohistochemical staining. Rousseau et al20 reported on the development of an epidermoid carcinoma on the buccal mucosa in an 82year-old woman, which appeared to occur shortly after she was started on etanercept.
Multiple adverse events have been reported in patients treated with biological agents, most of which have been associated with TNF-a inhibitors, as would be expected, because they are the most commonly used group. Adverse events include infections, reactivation of TB, congestive heart failure, liver failure, demyelinating disease, drug-induced lupus, autoantibody induction, and injection-site reactions.6 There also have been reports of an increase in the risk of malignancy, although the literature is conflicting and randomized control trials have provided no definitive evidence.7 There has been a particular focus on lymphoma, with some studies showing a statistical significant increase in the rate of lymphomas in patients with RA treated with TNF-a inhibitors.8 Conversely, an analysis of the National Data Bank for Rheumatic Diseases showed no increased incidence of lymphoma in patients receiving anti-TNF plus methotrexate compared with patients receiving methotrexate alone.9 Studies looking at lymphoma risk in patients with RA treated with TNF-a inhibitors are complicated by the fact that patients with RA are already at increased risk of developing lymphoma and that the risk appears to increase with disease severity.10 A meta-analysis involving 5,014 patients and looking at infliximab and adalimumab use in patients with RA did show an increased risk of serious infections and a dose-dependent increased risk of malignancies (including basal cell carcinoma, squamous cell carcinoma [SCC], and lymphoma).11 There have been multiple reports of an apparent association between etanercept and rapid development of cutaneous SCC.12,13 Brewer et al14 reported on 4 patients who were treated with etanercept for psoriasis and psoriatic arthritis and developed cutaneous SCCs, in some cases up to 19 SCCs, shortly after initiation of therapy. The average time to onset of SCC after commencement of treatment with etanercept was 11 months. Smith and Skelton15 in 2001 described the rapid onset of cutaneous SCC in 7 patients shortly after initiation of etanercept therapy. In contrast, Leb wohl et al16 found no association between etanercept and an increase in cutaneous SCC.
Oral Cancer and TNF-a Inhibitors There have been several reports of oral cancer developing in patients treated with TNF-a inhibitors. Our institution has previously reported on 2 such patients. The first patient presented with an SCC on the ventral tongue. She was taking etanercept injections at that time, but also had been treated previously with infliximab and adalimumab. The second patient,
Report of Case A 55-year-old woman was referred to the Department of Oral and Maxillofacial Surgery at the Dublin Dental University Hospital (Dublin, Ireland) complaining of severe pain in the right mandible. She reported that she had been referred by her general dental practitioner to a private oral surgeon 2 months previously, because she had been experiencing pain in the lower right third molar region. The oral surgeon reported no caries in the lower right third molar, no evidence of any soft tissue ulceration, no neurosensory deficits, and that the pain appeared to be consistent with a diagnosis of pericoronitis. Figure 1 shows a conebeam computed tomogram of the lower right third molar. As a result, the patient had surgical removal of the impacted lower third molar carried out under general anesthesia. The oral surgeon who performed the surgery reported that although it was a very difficult extraction, no questionable tissue was encountered and the bone around the tooth appeared sound during the procedure, indicating no bone resorption. Therefore, he did not suspect anything sinister and no tissue samples were taken. After the surgery, she developed delayed healing of the extraction socket, which was managed with antiseptic packs and antibiotics. Figure 2 shows a radiograph of the extraction socket after surgery. Nonetheless, she experienced ongoing pain in the right mandible and was referred to the Dublin Dental University Hospital for a second opinion. The patient had a history of RA, which had been treated with methotrexate for 3 years and adalimumab (Humira) injections for the previous 9 months. She also had previously taken alendronic acid for 1 year. She was a nonsmoker and drank 3 U of alcohol a week. There was no family history of oral cancer.
2138
ORAL SQUAMOUS CELL CARCINOMA AND ADALIMUMAB
FIGURE 1. Cone-beam computed tomogram of the mandible before surgical removal of the third molar. Beattie, Stassen, and Ekanayake. Oral Squamous Cell Carcinoma and Adalimumab. J Oral Maxillofac Surg 2015.
On examination she had limited mouth opening and tender right submandibular lymphadenopathy. Intraorally, there was a cavity in the lower right third molar region, which was filled with granulation tissue. She
was reporting decreased sensation over the distribution of the right lingual nerve, which was attributed to her recent third molar surgery. She was reporting no inferior dental nerve neuropathy.
FIGURE 2. Orthopantomogram after surgical removal of the lower right third molar. Beattie, Stassen, and Ekanayake. Oral Squamous Cell Carcinoma and Adalimumab. J Oral Maxillofac Surg 2015.
2139
BEATTIE, STASSEN, AND EKANAYAKE
An initial diagnosis of bisphosphonate-related osteonecrosis of the mandible or an unusual infection and delayed postoperative healing was made in light of her medication history of alendronic acid, methotrexate, and adalimumab. The patient was prescribed a 2-week course of clindamycin. On review 2 weeks later, there had been no improvement in her symptoms, and she continued to report severe pain in the right mandible. A decision was made to explore and examine a biopsy specimen from the lower right third molar region. The histology report showed a moderately differentiate keratinizing SCC. She had a hemimandibulectomy and partial glossectomy, neck dissection, and reconstruction with a fibula flap for a T4N0M0 SCC (Fig 3). She received postoperative radiotherapy. On review, 1 year post surgery, the patient was doing well and there was no evidence of recurrence. She is no longer taking adalimumab or any other medication for RA.
Discussion There are many case reports in the literature of malignancies occurring in patients taking TNF-a inhibitors, but there is no definitive evidence. The appearance in this case of an oral SCC in a patient with no other known risk factors, such as smoking or alcohol, suggests her treatment with adalimumab was a potential causative factor. The present patient had been taking adalimumab for 9 months. The patient described by Rahman et al17 in 2012 had been taking adalimumab for 15 months before presenting with carcinoma in situ in the buccal
mucosa. In the case reported by Leao et al,18 the patient had been taking adalimumab for 5 months and was found to have severe dysplasia on the lateral border of the tongue. There was an absence of other known risk factors for SCC in all these patients. Oral epithelial dysplasia and oral SCC have been associated with iatrogenic immunosuppression. Patients after kidney transplantation have been reported to have an increased risk of lip cancer.21 There also have been reports of increased risk of oral malignancy in patients taking azathioprine.22,23 It has been suggested that TNF-a could play a part in both the enhancement and inhibition of cancer development. TNF-a has a critical role in the induction of apoptosis and suppressive effects on gene expression, which could be important in tumor suppression. Inhibition of these functions has been suggested as a possible mechanism for increased risk of malignancy in patients taking TNF-a inhibitors.7 Conversely, chronic inflammation is thought to potentiate the development of certain cancers. One of the many functions of TNF-a is to promote angiogenesis, which is important in tumor growth and metastasis. TNF-a inhibitors might decrease the risk of cancer development by decreasing inflammation and suppressing angiogenesis.7,24 In some case reports, it is noticeable that tumors appeared quickly after the commencement of TNF-a inhibitors, raising the possibility that they were present subclinically before starting treatment.15,19 Potentially, TNF-a might have a different function at different stages of neoplastic disease progression.17
FIGURE 3. Orthopantomogram after mandibular resection and reconstruction with a fibula flap. Beattie, Stassen, and Ekanayake. Oral Squamous Cell Carcinoma and Adalimumab. J Oral Maxillofac Surg 2015.
2140 This case was an unusual presentation of an oral SCC. Diagnosis was complicated by the history of a difficult third molar extraction, the clinical appearance of a nonhealing socket, and the medication history that included oral bisphosphonates. The patient also was taking methotrexate, and there have been reports that the immunosuppressive effects of this drug can increase the risk of osteonecrosis developing in a patient taking bisphosphonates.25 Methotrexate has been implicated in the suppression of bone turnover.26 The American Association of Oral and Maxillofacial Surgeons has recently recommended widening the nomenclature of bisphosphonate-related osteonecrosis of the jaws to medication-related osteonecrosis of the jaw (MRONJ) to account for the growing number of osteonecrosis cases associated with other antiresorptive and antiangiogenic medications. Denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor-kB ligand used in the treatment of osteoporosis, has already been associated with MRONJ,27 and there have been several recent case reports proposing a link between other biologic agents and osteonecrosis of the jaws.28 Preidl et al29 in 2014 reported a case of osteonecrosis of the jaws in a patient taking adalimumab. The potential for adalimumab and methotrexate to impair defenses against infection made an unusual infection another possible diagnosis in this case.6,26 It also seems probable that there was an initial misdiagnosis made in attributing the pain in the right mandible to pericoronitis. It seems likely that the pain reported to the general dental practitioner was due to the malignant process in the mandible, rather than the presence of a pathology-free impacted third molar. The time delay in initiating more aggressive treatment is unfortunate and only serves to underline the need to consider all possible diagnoses, even in the presence of a common causative factor, such as an impacted third molar. This case highlights the difficulty in making a diagnosis in a patient taking multiple medications that have potential causative side-effects. It also highlights the need to rule out oral malignancy as a possible diagnosis in any patient with oral symptoms taking a TNFa inhibitor. There is no clear evidence supporting the role of TNF-a inhibitors in the development of oral SCC. However, there have been a series of case reports of the development of oral SCC in patients receiving these therapies in the absence of other meaningful risk factors. It would be prudent to screen and monitor these patients and to consider malignancy as a diagnosis in patients taking TNF-a inhibitors, even when presenting with atypical symptoms.
ORAL SQUAMOUS CELL CARCINOMA AND ADALIMUMAB
References 1. Furst DE, Keystone EC, Fleischmann R, et al: Updated consensus statement on biological agents for the treatment of rheumatic diseases. Ann Rheum Dis 69(suppl 1):i2, 2009 2. Breedveld FC, Weisman MH, Kavanaugh AF, et al: The PREMIER study: A multicentre, randomised double blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone. Arthritis Rheum 54:26, 2006 3. O’Neill ID, Scully C: Biologics in oral medicine: Principles of use and practical considerations. Oral Dis 18:525, 2012 4. Chong B, Wong H: Immunobiologics in the treatment of psoriasis. Clin Immunol 123:129, 2007 5. Scott DL, Kingsley GH: Tumour necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med 355:704, 2006 6. Scheinfeld N: A comprehensive review and evaluation of the side effects of the tumour necrosis factor alpha blockers etanercept, infliximab and adalimumab. J Dermatolog Treat 15:280, 2004 7. Solomon DH, Mercer E, Kavanaugh A: Observational studies on the risk of cancer associated with TNF-inhibitors in RA: A review of their methodologies and results. Arthritis Rheum 64:21, 2012 8. Geborek P, Bladstrom A, Turesson C, et al: Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 64:699, 2005 9. Wolfe F, Michaud K: The effect of methotrexate and anti-tumour necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum 58:1433, 2007 10. Baecklund E, Askling J, Rosenquist R, et al: Rheumatoid arthritis and malignant lymphomas. Curr Opin Rheumatol 16:254, 2004 11. Bongartz T, Sutton AJ, Sweeting MJ, et al: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: Systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295: 2275, 2006 12. Ly L, Czarnecki D: The rapid onset of multiple squamous cell carcinomas during etanercept treatment for psoriasis [letter]. Br J Dermatol 157:1076, 2007 13. Comte C, Guilhou JJ, Guillot B, et al: Rapid onset and fatal outcome of two squamous cell carcinomas of the genitalia in a patient treated with etanercept for cutaneous psoriasis [letter]. Dermatology 217:284, 2008 14. Brewer JD, Schott A, Roenigk R: Multiple squamous cell carcinomas in the setting of psoriasis treated with etanercept: A report of four cases and review of the literature. Int J Dermatol 50:1555, 2011 15. Smith KJ, Skelton HG: Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor alpha receptor IgG1-Fc fusion complex therapy. J Am Acad Dermatol 45:953, 2001 16. Lebwohl M, Blum R, Berkowitz E, et al: No evidence for increased risk of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis receiving etanercept for up to 5 years. Arch Dermatol 141:861, 2005 17. Rahman N, Healy C, Flint SR, et al: Cautionary note: A possible association between oral squamous cell carcinoma and tumor necrosis factor antagonists; need for oral screening. J Clin Rheumatol 16:197, 2010 18. Leao JC, Duarte A, Gueiros LA, et al: Severe oral epithelial dysplasia in a patient receiving adalimumab therapy. J Oral Pathol Med 34:447, 2005 19. Chainani-Wu N, Chang C, Gross AJ, et al: Oropharyngeal carcinoma arising after methotrexate and etanercept therapy for rheumatoid arthritis. Oral Surg Oral Med Oral Pathol Oral Radiol 117:e261, 2014 20. Rousseau A, Taberne R, Siberchicot F, et al: Cancer of the cheek in a patient under etanercept. Rev Stomatol Chir Maxillofac 110: 306, 2009
BEATTIE, STASSEN, AND EKANAYAKE 21. King GN, Healy CM, Glover MT, et al: Increased prevalence of dysplastic and malignant lip lesions in renal transplant recipients. N Engl J Med 332:1052, 1995 22. Van Leeuwen MT, Grulich AE, McDonald SP, et al: Immunosuppression and other risk factors for lip cancer after kidney transplantation. Cancer Epidemiol Biomarkers Prev 18:561, 2009 23. 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 15:185, 2003 24. Grivennikov SI, Greten FR, Karin M: Immunity, inflammation, and cancer. Cell 140:883, 2010 25. Alsalleeh F, Keippel J, Adams L, et al: Bisphosphonate associated osteonecrosis of jaw recurrence after methotrexate therapy. J Endod 40:1505, 2014
2141 26. Neto NC, Bastos A, Chierici-Marcantonia EM: Is rheumatoid arthritis a risk factor for oral bisphosphonate induced osteonecrosis of jaws? Med Hypotheses 77:905, 2011 27. Qi WX, Tang LN, He AN, et al: Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: A meta-analysis of seven randomized controlled trials. Int J Clin Oncol 19: 403, 2014 28. Ebker T, Rech J, von Wilmomsky C, et al: Fulminant course of osteonecrosis of the jaw in rheumatoid arthritis patient following oral bisphosphonate intake and biologic therapy [letter]. Rheumatology 52:218, 2013 29. Preidl R, Ebker T, Raithel M, et al: Osteonecrosis of the jaw in a Crohn’s disease patient following a course of bisphosphonate and adalimumab therapy. BMC Gasteroenterol 14:6, 2014
which include T-lymphocyte modulators, such as alefacept, and B-lymphocyte modulators, such as rituximab.3 The most commonly used biological agents are the TNF-a inhibitors, of which there are currently 3 licensed for use: adalimumab, etanercept, and infliximab. TNF-a is a proinflammatory cytokine. It mediates many inflammatory processes, including immune cell activation and proliferation, apoptosis, and regulation of leucocyte movement and adhesion. It is crucial in driving the inflammatory process and recruiting to sites of tissue inflammation. TNF-a inhibitors bind soluble and membrane-bound TNF-a, blocking its effects on target inflammatory cells.4 Adalimumab (Humira; AbbVie, Inc, North Chicago, IL) is a humanized monoclonal antibody, infliximab (Remicade; Janssen Biotech, Titusville, NJ) is a chimeric monoclonal antibody composed of human and murine regions and etanercept (Enbrel; Amgen, Inc, Thousand Oaks, CA) is a recombinant human TNF receptor fusion protein.5
Received from the Department of Oral and Maxillofacial Surgery and
Dublin Dental University Hospital, Lincoln Place, Dublin 2, Ireland;
Oral Medicine, Dublin Dental University Hospital, Dublin, Ireland. *Registrar in Oral Surgery.
e-mail: [email protected] Received March 23 2015
yProfessor and Consultant Oral and Maxillofacial Surgeon.
Accepted May 17 2015
zAssociate Professor and Consultant Oral and Maxillofacial
Ó 2015 American Association of Oral and Maxillofacial Surgeons
Surgeon.
0278-2391/15/00606-0
Address correspondence and reprint requests to Ms Beattie:
http://dx.doi.org/10.1016/j.joms.2015.05.022
Department of Oral and Maxillofacial Surgery and Oral Medicine,
2136
BEATTIE, STASSEN, AND EKANAYAKE
2137
Reports of Adverse Events
who was taking adalimumab, was found to have carcinoma in situ in the right buccal mucosa. Neither patient had any other known risk factors for SCC.17 Leao et al18 reported the case of a 39-year-old woman who had been taking adalimumab and who presented with a white patch on the lateral border of the tongue, which histology confirmed to be severe dysplasia. There was an absence of any other risk factors for dysplasia. Chainani-Wu et al19 reported on a 45-year-old man who had been taking etanercept for 5 months for RA and presented with a poorly differentiated T2N2bM0 SCC of the left tonsil. It should be noted that the patient was a smoker and that the tumor was positive for p16 immunohistochemical staining. Rousseau et al20 reported on the development of an epidermoid carcinoma on the buccal mucosa in an 82year-old woman, which appeared to occur shortly after she was started on etanercept.
Multiple adverse events have been reported in patients treated with biological agents, most of which have been associated with TNF-a inhibitors, as would be expected, because they are the most commonly used group. Adverse events include infections, reactivation of TB, congestive heart failure, liver failure, demyelinating disease, drug-induced lupus, autoantibody induction, and injection-site reactions.6 There also have been reports of an increase in the risk of malignancy, although the literature is conflicting and randomized control trials have provided no definitive evidence.7 There has been a particular focus on lymphoma, with some studies showing a statistical significant increase in the rate of lymphomas in patients with RA treated with TNF-a inhibitors.8 Conversely, an analysis of the National Data Bank for Rheumatic Diseases showed no increased incidence of lymphoma in patients receiving anti-TNF plus methotrexate compared with patients receiving methotrexate alone.9 Studies looking at lymphoma risk in patients with RA treated with TNF-a inhibitors are complicated by the fact that patients with RA are already at increased risk of developing lymphoma and that the risk appears to increase with disease severity.10 A meta-analysis involving 5,014 patients and looking at infliximab and adalimumab use in patients with RA did show an increased risk of serious infections and a dose-dependent increased risk of malignancies (including basal cell carcinoma, squamous cell carcinoma [SCC], and lymphoma).11 There have been multiple reports of an apparent association between etanercept and rapid development of cutaneous SCC.12,13 Brewer et al14 reported on 4 patients who were treated with etanercept for psoriasis and psoriatic arthritis and developed cutaneous SCCs, in some cases up to 19 SCCs, shortly after initiation of therapy. The average time to onset of SCC after commencement of treatment with etanercept was 11 months. Smith and Skelton15 in 2001 described the rapid onset of cutaneous SCC in 7 patients shortly after initiation of etanercept therapy. In contrast, Leb wohl et al16 found no association between etanercept and an increase in cutaneous SCC.
Oral Cancer and TNF-a Inhibitors There have been several reports of oral cancer developing in patients treated with TNF-a inhibitors. Our institution has previously reported on 2 such patients. The first patient presented with an SCC on the ventral tongue. She was taking etanercept injections at that time, but also had been treated previously with infliximab and adalimumab. The second patient,
Report of Case A 55-year-old woman was referred to the Department of Oral and Maxillofacial Surgery at the Dublin Dental University Hospital (Dublin, Ireland) complaining of severe pain in the right mandible. She reported that she had been referred by her general dental practitioner to a private oral surgeon 2 months previously, because she had been experiencing pain in the lower right third molar region. The oral surgeon reported no caries in the lower right third molar, no evidence of any soft tissue ulceration, no neurosensory deficits, and that the pain appeared to be consistent with a diagnosis of pericoronitis. Figure 1 shows a conebeam computed tomogram of the lower right third molar. As a result, the patient had surgical removal of the impacted lower third molar carried out under general anesthesia. The oral surgeon who performed the surgery reported that although it was a very difficult extraction, no questionable tissue was encountered and the bone around the tooth appeared sound during the procedure, indicating no bone resorption. Therefore, he did not suspect anything sinister and no tissue samples were taken. After the surgery, she developed delayed healing of the extraction socket, which was managed with antiseptic packs and antibiotics. Figure 2 shows a radiograph of the extraction socket after surgery. Nonetheless, she experienced ongoing pain in the right mandible and was referred to the Dublin Dental University Hospital for a second opinion. The patient had a history of RA, which had been treated with methotrexate for 3 years and adalimumab (Humira) injections for the previous 9 months. She also had previously taken alendronic acid for 1 year. She was a nonsmoker and drank 3 U of alcohol a week. There was no family history of oral cancer.
2138
ORAL SQUAMOUS CELL CARCINOMA AND ADALIMUMAB
FIGURE 1. Cone-beam computed tomogram of the mandible before surgical removal of the third molar. Beattie, Stassen, and Ekanayake. Oral Squamous Cell Carcinoma and Adalimumab. J Oral Maxillofac Surg 2015.
On examination she had limited mouth opening and tender right submandibular lymphadenopathy. Intraorally, there was a cavity in the lower right third molar region, which was filled with granulation tissue. She
was reporting decreased sensation over the distribution of the right lingual nerve, which was attributed to her recent third molar surgery. She was reporting no inferior dental nerve neuropathy.
FIGURE 2. Orthopantomogram after surgical removal of the lower right third molar. Beattie, Stassen, and Ekanayake. Oral Squamous Cell Carcinoma and Adalimumab. J Oral Maxillofac Surg 2015.
2139
BEATTIE, STASSEN, AND EKANAYAKE
An initial diagnosis of bisphosphonate-related osteonecrosis of the mandible or an unusual infection and delayed postoperative healing was made in light of her medication history of alendronic acid, methotrexate, and adalimumab. The patient was prescribed a 2-week course of clindamycin. On review 2 weeks later, there had been no improvement in her symptoms, and she continued to report severe pain in the right mandible. A decision was made to explore and examine a biopsy specimen from the lower right third molar region. The histology report showed a moderately differentiate keratinizing SCC. She had a hemimandibulectomy and partial glossectomy, neck dissection, and reconstruction with a fibula flap for a T4N0M0 SCC (Fig 3). She received postoperative radiotherapy. On review, 1 year post surgery, the patient was doing well and there was no evidence of recurrence. She is no longer taking adalimumab or any other medication for RA.
Discussion There are many case reports in the literature of malignancies occurring in patients taking TNF-a inhibitors, but there is no definitive evidence. The appearance in this case of an oral SCC in a patient with no other known risk factors, such as smoking or alcohol, suggests her treatment with adalimumab was a potential causative factor. The present patient had been taking adalimumab for 9 months. The patient described by Rahman et al17 in 2012 had been taking adalimumab for 15 months before presenting with carcinoma in situ in the buccal
mucosa. In the case reported by Leao et al,18 the patient had been taking adalimumab for 5 months and was found to have severe dysplasia on the lateral border of the tongue. There was an absence of other known risk factors for SCC in all these patients. Oral epithelial dysplasia and oral SCC have been associated with iatrogenic immunosuppression. Patients after kidney transplantation have been reported to have an increased risk of lip cancer.21 There also have been reports of increased risk of oral malignancy in patients taking azathioprine.22,23 It has been suggested that TNF-a could play a part in both the enhancement and inhibition of cancer development. TNF-a has a critical role in the induction of apoptosis and suppressive effects on gene expression, which could be important in tumor suppression. Inhibition of these functions has been suggested as a possible mechanism for increased risk of malignancy in patients taking TNF-a inhibitors.7 Conversely, chronic inflammation is thought to potentiate the development of certain cancers. One of the many functions of TNF-a is to promote angiogenesis, which is important in tumor growth and metastasis. TNF-a inhibitors might decrease the risk of cancer development by decreasing inflammation and suppressing angiogenesis.7,24 In some case reports, it is noticeable that tumors appeared quickly after the commencement of TNF-a inhibitors, raising the possibility that they were present subclinically before starting treatment.15,19 Potentially, TNF-a might have a different function at different stages of neoplastic disease progression.17
FIGURE 3. Orthopantomogram after mandibular resection and reconstruction with a fibula flap. Beattie, Stassen, and Ekanayake. Oral Squamous Cell Carcinoma and Adalimumab. J Oral Maxillofac Surg 2015.
2140 This case was an unusual presentation of an oral SCC. Diagnosis was complicated by the history of a difficult third molar extraction, the clinical appearance of a nonhealing socket, and the medication history that included oral bisphosphonates. The patient also was taking methotrexate, and there have been reports that the immunosuppressive effects of this drug can increase the risk of osteonecrosis developing in a patient taking bisphosphonates.25 Methotrexate has been implicated in the suppression of bone turnover.26 The American Association of Oral and Maxillofacial Surgeons has recently recommended widening the nomenclature of bisphosphonate-related osteonecrosis of the jaws to medication-related osteonecrosis of the jaw (MRONJ) to account for the growing number of osteonecrosis cases associated with other antiresorptive and antiangiogenic medications. Denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor-kB ligand used in the treatment of osteoporosis, has already been associated with MRONJ,27 and there have been several recent case reports proposing a link between other biologic agents and osteonecrosis of the jaws.28 Preidl et al29 in 2014 reported a case of osteonecrosis of the jaws in a patient taking adalimumab. The potential for adalimumab and methotrexate to impair defenses against infection made an unusual infection another possible diagnosis in this case.6,26 It also seems probable that there was an initial misdiagnosis made in attributing the pain in the right mandible to pericoronitis. It seems likely that the pain reported to the general dental practitioner was due to the malignant process in the mandible, rather than the presence of a pathology-free impacted third molar. The time delay in initiating more aggressive treatment is unfortunate and only serves to underline the need to consider all possible diagnoses, even in the presence of a common causative factor, such as an impacted third molar. This case highlights the difficulty in making a diagnosis in a patient taking multiple medications that have potential causative side-effects. It also highlights the need to rule out oral malignancy as a possible diagnosis in any patient with oral symptoms taking a TNFa inhibitor. There is no clear evidence supporting the role of TNF-a inhibitors in the development of oral SCC. However, there have been a series of case reports of the development of oral SCC in patients receiving these therapies in the absence of other meaningful risk factors. It would be prudent to screen and monitor these patients and to consider malignancy as a diagnosis in patients taking TNF-a inhibitors, even when presenting with atypical symptoms.
ORAL SQUAMOUS CELL CARCINOMA AND ADALIMUMAB
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