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Background Renal-transplant recipients are known to have increased rates of skin cancer associated with exposure to the sun. Little is known, however, about the prevalence and histologic features of lesions of the lips in these patients, or about risk factors for such lesions.
Methods We examined the lips of 160 renal-transplant recipients (105 men and 55 women; mean [±SD] age, 48±13 years) and 160 normal subjects matched with the transplant recipients for age, sex, and skin type. The mean length of time between transplantation and the examination was 69±52 months; 58 percent of the recipients had received their grafts more than 60 months earlier.
Results Among the 160 renal-transplant recipients, 21 (13 percent) had leukoplakia; in 2 (1.2 percent) the leukoplakia contained squamous-cell carcinoma. In contrast, only one normal subject (0.6 percent) had leukoplakia. Histologically, 13 of the 21 leukoplakias (62 percent) in the renal-transplant recipients who underwent biopsy were dysplastic, and 2 (10 percent) contained squamous-cell carcinoma. Actinic change was evident in 91 percent of the dysplastic lesions but not in the nondysplastic lesions (P<0.001). Exposure to the sun and smoking were risk factors for dysplastic and malignant lip lesions in the renal-transplant recipients (P<0.001 and P = 0.003, respectively). Among these recipients, only men had dysplastic or malignant lip lesions (P = 0.006); lipstick was used frequently by 73 percent of the women. The clinical appearance of lip lesions did not predict the presence of dysplasia or cancer.
Conclusions Renal-transplant recipients have an increased prevalence of leukoplakia, dysplasia, and cancer of the lip.
Methods
The study was conducted with the approval of the ethics committee of Tower Hamlets Health Authority and with the informed consent of the study subjects. We examined the lips of 160 consecutive renal-transplant recipients (105 men and 55 women; mean [±SD] age, 48±13 years) who were seen in an oral-screening clinic after a routine follow-up appointment in the renal clinic. The mean length of time since transplantation was 69±52 months.
Eight patients (5 percent) were receiving only cyclosporine. Of the remainder, those who underwent transplantation before 1985 (17 percent) were receiving prednisolone and azathioprine, and those who received transplants during or after 1985 (78 percent) were receiving prednisolone, azathioprine, and cyclosporine. The recipients were categorized according to lifetime sun exposure. Those who had lived in a tropical or subtropical region for more than three months or had worked in an outdoor occupation in the United Kingdom for five or more years were assigned to the highest sun-exposure group. Those who sunbathed more than 14 days per year or participated in outdoor activities more than 10 hours per week were assigned to the moderate-sun-exposure group. All others were assigned to the low-sun-exposure group. There was no difference in sun exposure between the male and female renal-transplant recipients. The women were asked how frequently they used lipstick when out of doors. All the subjects were assigned to one of five skin-type categories on the basis of their race or ethnic group, tanning ability, and tendency to burn, according to the classification of Fitzpatrick.9 The transplant recipients were also asked about their past and present smoking habits and their current alcohol consumption.
We also studied 160 consecutively recruited normal subjects who came to the Dental Institute at the Royal London Hospital for general dental treatment. These subjects (105 men and 55 women; mean [±SD] age, 50±15 years) were matched for age, sex, and skin type with the renal-transplant recipients.
The lips of all subjects were examined once by two clinicians who had previously reviewed the subjects' medical histories. The diagnosis of leukoplakia was made by the two clinicians conjointly according to the World Health Organization definition of leukoplakia as a keratotic white plaque that could not be removed and could not be characterized clinically or pathologically as indicative of any other disease.10 All lesions were photographed.
Pathological Studies
All clinically evident lesions were sampled at biopsy and examined histopathologically. Changes in the epithelium and connective tissue were assessed, and a diagnosis was made by a pathologist who had no knowledge of the subject's clinical history. Hyperkeratosis was considered to be present if the thickness of keratin was greater than is normally found on the vermilion surface of the lip. Epithelial dysplasia was defined by the presence of epithelial atypia without invasion of connective tissue, a bulbous rete-peg pattern, basal-cell crowding, abnormal mitotic activity, an increased ratio of nucleus to cytoplasm, and nuclear hyperchromatism. Squamous-cell carcinoma was diagnosed if multiple bud-like projections and discrete islands and nests of cells had invaded the underlying connective tissue. Actinic change was diagnosed when there was mild or marked loss of collagen fibers with an amorphous appearance and hyalinization in the underlying connective tissue. The inflammatory response in the connective tissue was also assessed.
Statistical Analysis
The photographs of the lip lesions were assessed separately by three experienced oral physicians who were unaware of the subject's clinical history, to determine the degree of agreement among observers and the degree of agreement between their diagnoses and the histologic diagnoses. The sensitivity and specificity of the clinical diagnoses as predictors of the histologic features of lesions were also determined. Differences between the groups were compared by the Mann–Whitney U test, in the case of continuous variables, and the chi-square test or Fisher's exact test for categorical variables. The analysis was repeated, comparing the transplant recipients who had dysplastic or malignant lesions with all other transplant recipients. In logistic-regression analyses, the presence or absence of dysplastic or malignant lesions was used as the dependent variable in order to examine the relation between dependent and explanatory variables. All statistical tests were two-tailed.
Results
Four percent of the renal-transplant recipients had received their grafts less than 12 months before the examination, 58 percent had received grafts more than 60 months previously, and 14 percent had received grafts more than 120 months previously. Twenty-three (14 percent) of the renal-transplant recipients (18 men and 5 women) had lip lesions; in the control group, only 1 subject (0.6 percent), a woman, had a lip lesion, diagnosed as leukoplakia. All the lesions affected the vermilion portion of the lower lip, except for a single carcinoma of the vermilion portion of the upper lip in a 62-year-old renal-transplant recipient, a man, with a history of smoking. The lip lesions were diagnosed clinically as leukoplakia in 21 of the transplant recipients and as papillomas in 2. Biopsies were performed on 21 of the lesions; the histopathological diagnosis was a fibroepithelial polyp in 1 patient, a papilloma in 1 patient (who also had epithelial dysplasia), benign hyperkeratosis in 7 patients, epithelial dysplasia in 11 patients (including 1 associated with a squamous-cell papilloma), and squamous-cell carcinoma in 2 patients (both men, 37 and 62 years old). Overall, 8 lip lesions were categorized as nondysplastic and 13 as dysplastic or malignant. No biopsy was done of two lip lesions, including a leukoplakia in a man whose renal transplant had been rejected and who was no longer receiving immunosuppressive therapy; this lesion disappeared one month after the initiation of dialysis. One woman, a transplant recipient with a clinically diagnosed papilloma of the lower lip, was lost to follow-up. The single leukoplakia in the normal subject had been present for many years without change. The characteristics of the two study groups and the distribution of risk factors among the renal-transplant recipients, subgroups of the recipients, and normal subjects are summarized in Table 1 and Table 2.
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There were no significant differences between the transplant recipients with dysplasia or cancer and those with normal lips or nondysplastic lesions with respect to age at time of transplantation, length of time since transplantation, type of immunosuppressive therapy, skin type, or alcohol consumption. No relation was found between lip dysplasia or cancer and the presence or number of atypical, dysplastic, or malignant skin lesions on the face.
There was significantly more sun exposure (P<0.001) and a higher frequency of smoking in the control group than in the renal-transplant group. The normal subjects smoked significantly more cigarettes per week than the transplant recipients, although both groups had smoked for the same mean number of years. Alcohol consumption was also significantly higher among the normal subjects than among the transplant recipients.
Histologically, 71 percent of the biopsy specimens from the transplant recipients showed pronounced hyperkeratosis; epithelial dysplasia was present in 52 percent, and 10 percent had evidence of squamous-cell carcinoma (Figure 2, Figure 4A, and Figure 4B). Actinic change was evident in 91 percent of the dysplastic lesions but was absent in the nondysplastic lesions in the recipients (P<0.001). A host inflammatory response was either absent or minimal in all nondysplastic lesions and 64 percent of the dysplastic lesions. There was no significant difference between the transplant recipients with dysplastic lesions and those with nondysplastic lesions with respect to the length of time since transplantation or the type of immunosuppressive therapy. In the two recipients with squamous-cell carcinoma, there was an unusual combination of keratin-pearl formation with aggressive infiltration and an absence of inflammatory response in the connective tissue.
Discussion
The prevalence of dysplastic lesions of the vermilion border of the lip in this group of renal-transplant recipients was 8 percent, and that of malignant lip lesions 1.2 percent; the control subjects had no such lesions. These prevalence rates were 90 and 15 times higher, respectively, than those reported in a recent, large general-population study of white North Americans.11 The prevalence of lip leukoplakia in the transplant recipients (13 percent) was 22 times higher than that in the normal subjects (0.6 percent) and 16 times higher than in the North American study (0.8 percent).11
The renal-transplant recipients and the controls were matched for age, sex, and skin type, but the renal-transplant group had a generally lower frequency of possible risk factors such as smoking, alcohol consumption, and exposure to the sun. Immunosuppression appears to have been the single most important cause of the higher prevalence of lip lesions in the transplant recipients, although not all were at equal risk for dysplastic or malignant lesions. Additional factors such as sun exposure may also be important, since lip cancer is often preceded by actinic keratosis and dysplasia.12,13 Indeed, exposure to the sun appears to have been an important factor in the development of dysplasia in the transplant recipients; 91 percent of the biopsy specimens with evidence of dysplasia also had actinic changes in the underlying corium, whereas there was no evidence of such changes in the biopsy specimens from recipients who did not have dysplasia (P<0.001). Moreover, the transplant recipients with dysplastic or malignant lip lesions had had significantly more exposure to the sun than those with normal or nondysplastic lesions (P<0.001); nearly 69 percent of those with dysplasia or lip cancer were in the highest sun-exposure group. Exposure to the sun and smoking were significant independent risk factors for the development of dysplastic or malignant lip lesions (P<0.01).
The transplant recipients with dysplasia or cancer of the lip did not have an increased incidence of cutaneous actinic keratoses and skin carcinomas of the face, a finding that suggests that independent processes may be involved in the development of skin and lip cancer. There was little histologic evidence of viral infection in the biopsy specimens we examined, but there is accumulating evidence that implicates human papillomaviruses in the pathogenesis of skin cancer in renal-transplant recipients.14,15,16,17
Although lip cancer in transplant recipients may be superficial, multiple, or atypical in appearance,18 a disturbing feature in this study was the innocent clinical appearance of these lesions. A high proportion (62 percent) of leukoplakias were dysplastic, and 10 percent had undergone malignant change. Furthermore, dysplastic changes were seen at some distance from the clinically obvious lesions.
Although the men and women in this study were otherwise well matched for important variables associated with the development of skin cancer, all the dysplastic lesions and squamous-cell carcinomas occurred in men. Since keratinocytic epidermal cancers are not related to hormonal activity,19 the use of a physical block against sun exposure — such as lipstick — is probably a factor that reduces the risk of lip cancer in women.
We are indebted to Mr. A. Cruchley for advice and encouragement.
Source Information
From the Departments of Oral Medicine and Periodontology (G.N.K., C.M.H., M.H.T.), Dermatology (M.T.G., I.M.L.), and Nephrology (J.T.C.K.), and the Joint Department of Oral Pathology with the Institute of Dental Surgery (D.M.W.), London Hospital Medical College, London, and the Department of Oral Health, University of Manchester, Manchester, United Kingdom (H.V.W.).
Address reprint requests to Dr. King at the Department of Oral Medicine and Periodontology, London Hospital Medical College, London E1 2AD, United Kingdom.
References
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