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Patch Testing in Oral Lichenoid Lesions of Uncertain Etiology

Lynch, Maeve MB, BCh, BAO, MRCPI*; Ryan, Aisling MB, BCh, BAO, BMedSc, MRCPI*; Galvin, Sheila BDent Sc, MFDS, MB, BCh, BAO, MRCPI; Flint, Stephen MA, PhD, BDS, FDS RCSEng, FFD RCSI, MBBS (Hons), FICD, FTCD; Healy, Claire M. MB, BCh, BDent Sc, FDS RCSEng (OM), FFD RCSI (OM), PhD; O’Rourke, Niamh BDent Sc, MFDS, MSc, MOrth; Lynch, Kathleen BDSNUI; Rogers, Sarah MD, MSc, FRCP, FRCPI*; Collins, Paul MD, FRCPI, DCH*

doi: 10.1097/DER.0000000000000109
STUDIES

Background The benefit of patch testing patients with oral lichenoid lesions (OLL) is still debated.

Objective We assessed the results of patch testing in patients with multiple amalgams and multiple OLL, where the etiology of the oral mucosal disease was unclear.

Methods Patients referred from an oral medicine clinic were patch tested to the British Society of Cutaneous Allergy standard series, dental and materials series, and, in 1 patient, the dental methacrylate series also. Patients’ responses to amalgam removal were assessed during a mean follow-up of 2.6 (range, 0–4.75) years.

Results Thirty-one patients with OLL were referred for patch testing. Ten (32%) patients tested positively to mercury. Eight patients with positive reactions to mercury had amalgam removal, with complete or partial resolution of the OLL in all cases (100%).

Conclusions Patients with OLL of unclear etiology adjacent to large amalgam restorations should be investigated for delayed contact hypersensitivity. Removal of amalgams in patients with positive patch test reactions to mercury results in improvement or resolution of the OLL in most patients.

From the *Charles Centre, Department of Dermatology, St Vincent’s University Hospital; and †Dublin Dental University Hospital, Ireland.

Address reprint requests to Maeve Lynch, MB, BCh, BAO, MRCPI, The Charles Centre, Department of Dermatology, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. E-mail: lynchmaeve@yahoo.ie.

Author Maeve Lynch received an unrestricted research grant from Merck, Sharp & Dohme.

The authors have no conflicts of interest to declare.

Oral lichenoid lesions (OLL) are often attributed to amalgam fillings. Many are easy to diagnose clinically and distinguish from idiopathic oral lichen planus (OLP) because of a direct topographic relationship to the amalgam restoration. Typical sites include the lateral borders of the tongue and the buccal mucosa. They are usually unilateral and asymmetrical. Common symptoms include pain and burning with spicy food. However, many are asymptomatic.

The etiology of OLL is complex, multifactorial, and incompletely understood. Corrosion of dental metals may result in sensitization of the oral mucosa and a T-celldependent, type IV hypersensitivity reaction.1 A less widely accepted explanation is that close contact between dissimilar metals may result in electrochemical reactions, releasing metal ions, resulting in damage to the oral mucosa.2 Direct traumatic effects and irritant effects of dental restorations also contribute to the development of OLL. Immunologic or toxic reactions to plaque accumulations on the surface of restorations have also been described and improve with oral hygiene.3 These reactions are localized to the area in direct contact with the inciting agent. Prolonged intimate contact of the oral mucosa with amalgam fillings seems to be necessary for a hypersensitivity reaction to occur.

Some patients have multiple amalgams and multiple lichenoid lesions. In this subset, it is difficult to determine whether the amalgam is associated with the OLL, via either an irritant or an allergic mechanism, or whether the OLL has an alternative etiology such as OLP. Distinguishing between OLP and OLL on histological grounds can prove difficult. In 1 study by Thornhill et al,4 the pathologists were only able to distinguish between the 2 conditions one third of the time. The value of patch testing remains controversial. Thornhill et al5 showed that a positive patch test and a close topographic relationship to amalgams were better predictors of improvement after amalgam replacement than either alone in OLL. However, Issa et al6 found patch testing to be of limited value and that close/direct clinical association was the best predictor of healing after amalgam replacement. Removal of amalgams is costly, time-consuming, and inconvenient for the patient.

We sought to confirm the usefulness of patch testing in a select group of patients with OLL of uncertain etiology.

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PATIENTS AND METHODS

We performed a retrospective study of patients with OLL who were referred from an oral medicine clinic for patch testing in 2007 and 2008. The patients referred for patch testing were patients with extensive lichenoid lesions and multiple amalgams where the etiology of the OLL was not clear. Patients with OLP or those with 1 OLL in association with 1 amalgam were not referred because the diagnosis of OLP or OLL was more clear-cut. The patients were identified from a clinical database and the medical histories were reviewed. Patients with evidence of dysplasia on oral mucosa biopsy without evidence of lichenoid inflammation were excluded. The patients were referred by 2 oral medicine consultants. IQ Ultra Chambers (Chemotechnique Diagnostics, Sweden) were applied to the patients’ backs and removed after 48 hours. The patients were tested to the British Society of Cutaneous Allergy standard series as well as a dental screening (Table 1) and amalgam (Table 2) series (Chemotechnique Diagnostics) and 1 patient was tested to the dental methacrylate series. Patch test results were read by 1 of the 2 consultant dermatologists experienced in patch testing. The readings were taken on days 2 and 4, and in many patients, the readings were taken on day 7. Macular reactions were graded as ±, papular reactions were graded as +, and papulovesicular reactions were graded as ++ in accordance with the International Contact Dermatitis Research Group criteria.7 The patients’ medical records were reviewed after patch testing to assess clinical progress in the oral medicine clinic. Photographic records were taken in most patients so that improvement in clinical appearance could be monitored. The mean duration of follow-up was 2.6 (range, 0–4.75) years.

Table 1

Table 1

Table 2

Table 2

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RESULTS

Thirty-six patients with OLL of uncertain etiology were referred from the oral medicine clinic to the dermatology clinic for patch testing. None had cutaneous lichen planus. Five patients were excluded because of the presence of dysplasia only on oral biopsy and 31 patients were included in the study. The mean age was 50.6 (range, 32–74) years, and 22 (71%) patients were women. Thirteen patients were asymptomatic. In those with symptoms, the duration of symptoms ranged from 3 weeks to 14 years. Thirty patients had amalgams in direct contact with the OLL and 1 patient had amalgams in close contact. Four patients were smokers, 8 patients were ex-smokers, and 19 patients were nonsmokers. The pattern of OLL was reticular in 24 patients, erosive/atrophic in 5 patients, and ulcerative in 2 patients. Six patients had clinical corrosion of the amalgams recorded. Four patients had a biopsy that showed lichenoid inflammation in all biopsies. In addition to lichenoid inflammation, there was evidence of mild dysplasia in 2 of the 4 biopsies.

Thirty patients were tested to the British Society of Cutaneous Allergy standard series, 31 patients were tested to the dental series (25 dental allergens), 31 patients were tested to the amalgam series (7 allergens), and 1 patient was tested to the methacrylate series (15 allergens). Twenty-two patients had readings on days 2 and 4, and 9 patients had readings on days 2, 4, and 7.

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Positive Reactions

Seventeen (53%) patients had a positive reaction to the dental or amalgam series. Seven (23%) patients had positive reactions to the British Society of Cutaneous Allergy standard series. Ten (32%) patients tested positively to mercury. Positive reactions are described in Table 3. Twelve (39%) patients had negative reactions to all of the series tested.

Table 3

Table 3

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Positive Reactions to Mercury

Of the 10 patients with positive reactions to mercury, 6 had a reticular pattern and 4 had an erosive/atrophic pattern of OLL. Four patients had clinically corroded amalgams. Eight of the 10 patients with a positive reaction had partial or complete replacement of amalgams (Table 4). There was complete resolution in 6 patients who had amalgam replacement (Figs. 1, 2). Clinical improvement was seen in 2 patients after amalgam replacement. Two patients did not have their amalgams replaced. One of these 2 patients’ OLL remained unchanged and the outcome is unknown in the other patient because she did not attend follow-up appointments. Of note, 2 of the 10 patients with positive reactions to mercury had a biopsy. Lichenoid inflammation with associated mild dysplasia was evident in both biopsies.

Table 4

Table 4

Figure 1

Figure 1

Figure 2

Figure 2

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Negative Reactions to Mercury

Of the 21 patients with negative reactions to mercury, 6 (29%) had their amalgams replaced; 1 patient had complete resolution of OLL, 3 patients improved, and 2 patients were unchanged. Two of the 3 patients who had a partial response to amalgam replacement had other relevant allergens including a positive reaction to 2% copper sulfate in 1 patient and a positive reaction to 1% camphorquinone (in composite) in 1 patient who had an amalgam replaced with a composite restoration before presentation (Table 5). Two patients with negative reactions to mercury remained unchanged after amalgam replacement and their diagnoses subsequently changed from OLL (1 of these patients has developed OLP associated with desquamative gingivitis and the other patient had a subsequent biopsy demonstrating moderate dysplasia and patchy lichenoid inflammation).

Table 5

Table 5

One patient with composite restorations and negative patch test results to all substances had teeth adjacent to the lesions extracted for dental reasons, which resulted in complete resolution of the reticular patch suggesting a lichenoid reaction to plaque or a false-negative patch test. The remaining 14 patients with negative reactions to mercury did not have their amalgams replaced. One patient’s OLL spontaneously resolved and 1 patient improved, whereas 7 patients remain unchanged. Two patients have been subsequently diagnosed as OLP on the basis of clinical developments and 3 patients did not attend follow-up after patch testing.

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DISCUSSION

The aim of this study was to determine the role of patch testing and subsequent amalgam replacement in patients with OLL where the cause of the OLL was unclear. The etiology of OLL was unclear because of the presence of extensive OLL and multiple amalgams. Thirty-one patients were patch tested. Ten patients had positive reactions to mercury. Eight of the 10 patients had amalgam replacement, with resolution of OLL in 6 patients and improvement in 2 patients. Our study confirms that, in patients with OLL of unclear etiology who have a positive patch test reaction to mercury, removing amalgams is worthwhile.

A contact allergy to mercury in amalgam confirmed by patch testing was described by Shovelton.8 Other metals in amalgams such as silver or tin are rarely implicated in allergic reactions.3 An oral lichenoid lesion related to dental amalgam typically has a clear anatomical relationship with the dental amalgam and usually affects the tongue or buccal mucosa.5 However, it can be difficult to distinguish OLP from OLL in some patients with extensive amalgams and extensive lesions. It is not practical to patch test all patients with OLL, but patch testing this subgroup of patients where the diagnosis is unclear is useful.

Studies evaluating the usefulness of patch testing in OLL have shown conflicting results.9 One reason for this is that many earlier studies evaluating patch testing have grouped OLP and OLL together as the same entity. Oral lichen planus is a more widespread condition involving many sites within the oral mucosa and may involve the skin and genital mucosa. Oral lichen planus is an immune-mediated disease and T cells are the main effector cells. Distinguishing both conditions is important for subsequent management. A recent prospective study to assess the prevalence of mucosal lesions in a population of patients with amalgam restorations found that OLL was associated with dental amalgam in 7 of the 100 patients assessed.10 Lesions were related to old and corroding amalgams.10

Patients in whom the OLL are intimately associated with the amalgam are much more likely to have positive patch test reactions to mercury than those with more extensive or noncontacting lesions.5 In the study of Thornhill et al,5 70% of patients with a very strong or strong association with their amalgams showed a positive patch test reaction to mercury or amalgam compared with only 3.9% of patients with a weak or no association. In 1 study, OLL in direct contact with the amalgam responded better to amalgam removal than OLL outside the contact zone.11 Patients with positive patch test reactions demonstrated a better response to amalgam removal.11 Issa et al6 demonstrated that, in 34 of 38 patients with OLL in a close topographic relationship to amalgams, marked or complete healing occurred after amalgam replacement.

In our study, 32% of the patients had positive patch test reactions to mercury versus 3.2%12 in the general population. Another study demonstrated similarly that, of 20 patients with OLL who received patch testing, 7 (35%) patients had positive reactions to mercury.13 The results of patch testing to mercury and amalgam can distinguish those who have contact allergy to these substances but will not define those with irritant or toxic allergy to these metals. Both groups are likely to benefit from amalgam removal.

In the study of Thornhill et al,5 93% of patients with OLL with a strong or very strong association with an amalgam restoration had an improvement in their lesions after amalgam replacement, whereas no improvement was seen in patients with OLP. A recent study of 44 patients demonstrated regression of OLL in 71% (n = 22) of patients after dental restorative materials were replaced. This response is in contrast to the improvement seen in only 8% (n = 1) of patients with OLP who had dental material replacement.13 Other studies have demonstrated contrasting results.12 A systematic review of the literature demonstrated response rates in OLL of 38% to 100% after amalgams were replaced.14 One study by Issa et al6 demonstrated marked improvement in 13 (81%) of 16 patients with negative patch tests. They found no statistically significant difference in healing in patients with positive and negative patch test results. Our study demonstrated that 100% of the patients with a positive patch test who had selected amalgam replacement demonstrated resolution or improvement of the OLL. This result confirms the usefulness of patch testing in patients with OLL of uncertain etiology. The duration of follow-up of patients with an average of 2.6 (range, 0–4.75) years may account for the high rate of response to amalgam replacement in our study. In the study by Issa et al,6 a minimum of 3 months was usually required for marked improvement or resolution to occur after amalgam replacement.

In patients with negative patch test results to mercury who had amalgam replacement, the improvement in OLL or resolution of OLL may be explained by the fact that 2 of the 4 patients had other relevant contact allergies to 2% copper sulfate and 1% camphorquinone (in a composite restoration), respectively. Little is known about the possible toxic or irritant reactions to other constituents in amalgam or to plaque, but it is possible that these reactions may also have played a role in the etiology of OLL in patients with negative patch test reactions who responded to amalgam replacement subsequently. It has been recommended, in the case of a negative patch test reaction but a strong suspicion of OLL associated with a dental amalgam, to initially replace a single-test amalgam with an alternative material to assess response.15 Patch testing is important to identify the cause of the OLL, if possible, and to identify potential replacement dental restoration materials in patients with positive patch test reactions.

A limitation of our study is the small number of patients involved. In addition, because it is retrospective, follow-up data are missing in some patients. Some patients have had their diagnoses changed to OLP or dysplasia when reviewed, which reflects what happens in real-life practice. Another limitation is that we did not use a validated measure to demonstrate the grade of improvement in OLL in the patients who improved after amalgam replacement. Resolution of OLL was complete and therefore clinically significant in 6 patients; improvement was noted in 2 of the 10 patients with positive patch test reactions to mercury after amalgam replacement.

The diagnosis is not always clear-cut in this select group of patients with multiple amalgams and multiple lesions, and patch testing is a useful investigation in establishing the diagnosis. Removing amalgam in those with positive patch test reactions to dental materials may not guarantee success, but positive outcome is more likely than in those with negative results. Partial or complete replacement of amalgams in patients with positive patch test reactions to dental metals demonstrated a clinical improvement or resolution of OLL in all patients in our experience. This is consistent with previous studies showing that replacement of amalgams with alternative materials in patients with a positive patch test reaction and amalgams in close clinical relationship to the OLL is more likely to result in resolution.

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