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JCR: Journal of Clinical Rheumatology:
doi: 10.1097/RHU.0b013e3181df8932
Concise Report

Cautionary Note: A Possible Association Between Oral Squamous Cell Carcinoma and Tumor Necrosis Factor Antagonists; Need for Oral Screening

Rahman, N. BA, B Dent Sc, MFDSRCSI*; Healy, C. B Dent Sc, MB BCh, FDSRCS Eng (OM), FFD RCSI, PhD*; Flint, Stephen R. MA, PhD, BDS, MBBS(Hons), FDSRCS(Eng), FFDRCSIre, FICD, FTCD*; Stassen, L. F. A. FRCS, FDSRCS, MA, FTCD, FFSEM (UK), FFDRCSI*†

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From the *Department of Oral and Maxillofacial Surgery and Oral Medicine, Dublin Dental School and Hospital, Trinity College Dublin, Ireland; and †National Maxillofacial Unit, St. James' Hospital, Dublin, Ireland.

Correspondence: Naomi Rahman, BA, B Dent Sc, MFDSRCS (I), Department of Oral and Maxillofacial Surgery, Dublin Dental School and Hospital, Trinity College Dublin, Lincoln Place, Dublin 2, Republic of Ireland. E-mail: naomirahman@hotmail.com.

Tumor necrosis factor (TNF) antagonists have been key medications in the treatment of rheumatic diseases since being approved by the Food and Drug Administration, initially in 1998.1 Yet these drugs have also been associated with some serious side effects, including lymphoma development.2 A number of articles have commented on the development of other malignant tumors, eg, nonmelanoma skin cancers in association with their use.3,4 We present 2 cases of patients taking TNF antagonists and the subsequent development of oral squamous cell carcinomas (SCC) and review the literature on the subject.

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CASE REPORTS

Case 1

A 55-year-old woman presented to the Oral Medicine Department. She was referred by her general dental practitioner, who noticed on routine examination, an indurated ulcer on the ventral surface of the tongue. She had a history of rheumatoid arthritis, diagnosed 12 years previously and had been taking phenyl acetic acid and methotrexate for 12 years, leflunomide for 1 month, and etanercept subcutaneous injections for 3 years, 25 mg twice weekly. She had previously taken systemic corticosteroids (prednisolone 20 mg) in 1995. She had taken infliximab in 2001, etanercept in 2003, and adalimumab in 2005 for short periods. She had never smoked and drank 1 glass of wine every 2 weeks.

On examination, a 2 × 2 cm ulcer on the left ventral surface of the tongue with induration was noted (Fig. 1). The appearance was strongly suggestive of an SCC. She was admitted for a full work-up. This included the following blood tests: full blood count, hematology, urea and electrolytes, liver function tests, calcium, glucose, and C-reactive protein. Magnetic resonance imaging, computed tomography, positron emission tomography (PET) scans, and an examination under general anesthesia of the head, neck, and abdominal region were also performed. The magnetic resonance imaging scan showed an area of high signal on the left hand side of the tongue, a 1.1-cm node in the left jugular chain, and loss of normal flow in the left internal jugular vein. Computed tomography scan showed one node <10 mm, adjacent to the carotid sheath and the left angle of the mandible. PET scan revealed the primary neoplasm on the tongue and the ipsilateral submandibular node that were both fludeoxyglucose-avid. She underwent excision of the lesion on the ventral surface of the tongue (partial glossectomy), which was reconstructed with a local flap and had a functional neck dissection (level I–IV on the left hand side). The final histology indicated a moderately differentiated invasive SCC, which invaded muscle and demonstrated extensive perineural infiltration. Metastatic carcinoma was found in 2 out of 17 left neck nodes with microscopic extracapsular spread. In view of the histology, a postsurgical course of radiotherapy was advised (50.4 Gy in 28 fractions). It was decided to modify the dose prescription of radiotherapy to take into account her long-standing rheumatoid arthritis. Her maintenance dose of methotrexate was discontinued during the course of radiation as it is a recognized normal tissue radio-sensitizer.

Figure 1
Figure 1
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After 22 months, a new SCC was noticed in a new site on the left lateral border of the tongue. A PET scan showed FDG uptake in the left lateral area but no metastasis. Initial biopsy indicated early invasive SCC. A partial glossectomy was undertaken and reconstructed with a nasolabial flap. The histology results confirmed SCC, size PT1 with complete excision and 0.5 cm clearance with dysplasia present at margins. She had been taking methotrexate over the 22 month period but no TNF antagonist. It has been 2 years and 3 months since her first diagnosis. Currently, the patient is doing well and is being closely monitored at monthly intervals.

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Case 2

A 61-year-old man was referred to the Oral Medicine Department by his general practitioner, with a lesion on the right buccal mucosa. The patient reported that he first noticed a white patch inside his right cheek 1 year previously. He had a history of hypertension, glaucoma, and rheumatoid arthritis, and was taking celecoxib, methotrexate, folic acid, and had received gold injections 10 years previously. He had commenced treatment with adalimumab, subcutaneous injections (40 mg once fortnightly) 15 months previously. He had stopped smoking 25 years ago, having smoked 4 cigarettes per day only for 15 years. He currently drank 15 units of alcohol per week.

On examination, a speckled white lesion with lichenoid features measuring 20 × 15 mm with a raised central nodule, measuring 6 × 5 mm, was found on the right buccal mucosa closely related to a full gold crown on the lower right first molar tooth (Fig. 2).

Figure 2
Figure 2
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A full blood count, antinuclear antibody titers, patch testing to the British Contact Dermatitis Series dental materials and a biopsy of the central nodule were undertaken. Initially topical steroid therapy (betamethasone mouthwash) elicited a good response. Blood results showed lymphopenia (0.8 × 109/L; normal range, 1.5–3.5 × 109/L). Histopathology revealed a pyogenic granuloma and patch testing elicited a negative response to gold sodium thiosulphate.

He was regularly reviewed, but 5 months later, an ulcerated region and atrophic area with slight induration was noted extending from the right buccal mucosa to the commissure (Fig. 3). A biopsy of the site showed carcinoma in situ at one edge of a dysplastic keratotic area with focal ulceration and an associated florid lichenoid tissue reaction. The lesion was resected with a 1-cm margin of clearance and reconstructed. One year later, an indurated raised lesion with central crusting, 1 cm in diameter was noticed under his right ear, which the patient felt had been present for a month. This was removed by excisional biopsy and the clinical suspicion of basal cell carcinoma (BCC) was confirmed on histopathology. His current rheumatoid arthritis regimen includes adalimumab and methotrexate and it has now been over 2 years since initial diagnosis with an oral SCC. Currently, the patient is well and attends for regular reviews on an oral mucosa dysplasia clinic.

Figure 3
Figure 3
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DISCUSSION

TNF is a remarkable molecule with both pro- and antitumor effects. TNF antagonists have been harnessed to treat numerous diseases including juvenile arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn disease.5 These drugs have had a beneficial effect in current treatment regimens of rheumatoid arthritis with or without the use of methotrexate.6

Scheinfeld carried out a comprehensive review of the side effects of TNF antagonists. These included the development of lymphoma, infections such as tuberculosis, congestive heart failure, demyelinating disease, drug-induced lupus, autoantibody induction, reactions at the injection site, and liver failure.7 In 2003, the Food and Drug Administration stated that the risk of malignancy development in patients receiving these drugs is unknown.8 Although patients with rheumatoid arthritis or severe psoriasis on no medication already have an increased risk of lymphoma and other types of malignant change, at present, there are 2 conflicting bodies of evidence in relation to malignancy development associated with anti-TNF medications. Some studies suggest that malignancy development does seem to occur with a dose-dependent increased risk.9

Articles discussing nonmelanoma skin cancer occurrence also reflect these disparate views. An early article by Smith and Skelton (2001) reported cases of 7 patients developing cutaneous SCC with rapid growth, all of whom had received etanercept therapy over a 2- to 4-month period.4 Two case reports in 2004 and 2008, respectively, discussed SCC development of the genitalia in 2 patients who were treated with etanercept for psoriasis.10,11 Chakravarty et al investigated the risk of developing a nonmelanoma skin cancer. They found that rheumatoid arthritis itself was associated with an increased risk of development of BCC and cutaneous SCC, and this risk increased if the patients were treated with prednisone or TNF inhibitors.3 Bongartz et al carried out a systematic review and meta-analysis on the risk of malignant change occurring and found evidence of a dose-dependent increased risk of malignancies such as lymphomas, BCC, and skin SCC, in patients on all anti-TNF medication (excluding etanercept) with concurrent rheumatoid arthritis.2

However, another double-blind trial evaluated etanercept compared with methotrexate treatment in patients with early rheumatoid arthritis over a 2-year period: 4 BCCs occurred in the etanercept group, but overall this was similar to age- and sex-matched groups in the general population.12,13 Lebwohl et al echoed this result finding; no evidence for an increased risk of cutaneous SCC in rheumatoid arthritis patients treated with etanercept for up to 5 years.14

There are no reported data on the development of oral SCC in patients on TNF antagonists. The known risk factors for development of intraoral SCCs include smoking,15 excess alcohol intake,16 betel nut chewing,17 oral submucous fibrosis, oral lichen planus,18 lupus, human papillomavirus,19 candida, and some rare congenital disorders such as Fanconi anemia or dyskeratosis congenita. Neither of our patients were smokers, although one had smoked minimally up to 25 years previously. Neither patient drank alcohol to excess. In 1 case, the lesion presented as a lichenoid area on the buccal mucosa that may have been related to the adjacent full gold crown, present for 10 years. However, patch testing to gold was negative and the close temporal relationship between the commencement of anti-TNF medications and the development of oral SCC is noteworthy. Metachronous primary disease is a feature of oral SCC, as was seen in patient 1.

In conclusion, currently there is no clear cut cause and effect relationship between the administration of a TNF antagonist and the onset of oral SCC. However, from our 2 reports, a tenuous link may be proposed. Patients receiving these therapies should have long-term follow-up to monitor for development of serious infections or neoplasms, including oral cancer. We recommend oral screening for all patients prior to commencing TNF antagonist medications and during and following therapy. Physicians prescribing these agents should liaise with dentists in this regard. More longitudinal studies are needed to clarify possible associations between these agents and the development of oral malignancy.

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REFERENCES

1. Khanna D, McMahon M, Furst DE. Safety of tumor necrosis factor-alpha antagonists. Drug Saf. 2004;27:307–324.

2. 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. 2006;295:2275–2485.

3. Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and tumor necrosis factor inhibitors. J Rheumatol. 2005;32:2130–2135.

4. 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. 2001;45:953–956.

5. Hochberg MC, Lebwohl MG, Plevy SE, et al. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum. 2005;34:819–836.

6. St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomised, controlled trial. Arthritis Rheum. 2004;50:3432–3443.

7. Scheinfeld N. A comprehensive review and evaluation of the side effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab. J Dermatolog Treat. 2004;15:280–294.

8. FDA Briefing Document. Update on the TNF-alpha blocking agents. Available at: http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930b1.htm.

9. Wolfe F, Michaud K. The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum. 2007;56:1433–1439.

10. Fryrear RS II, Wiggins AK, Sangueza, et al. Rapid onset of cutaneous squamous cell carcinoma of the penis in a patient with psoriasis on etanercept therapy. J Am Acad Dermatol. 2004;51:1026.

11. 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. Dermatology. 2008;217:284–285.

12. Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002;46:1443–1450.

13. Bongartz T, Warren FC, Mines D, et al. Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials. Ann Rheum Dis. 2009;68:1177–1183.

14. 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. 2005;141:861–864.

15. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum. 2004;83:1–1438.

16. IARC Monographs Working Group on Alcoholic Beverage Consumption and Ethyl Carbamate (Urethane); February 6–13, 2007. Available at: http://monographs.iarc.fr/ENG/Meetings/vol96-summary.pdf.

17. Merchant A, Husain SS, Hosain M, et al. Paan without tobacco: an independent risk factor for oral cancer. Int J Cancer. 2000;86:128–131.

18. Koch P, Balmer FA. Oral lesions and symptoms related to metals used in dental restorations: a clinical, allergological, and histologic study. J Am Acad Dermatol. 1999;41:422–430.

19. McKaig RG, Baric RS, Olshan AF. Human papillomavirus and head and neck cancer: epidemiology and molecular biology. Head Neck. 1998;20:250–265.

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