Case Description. The authors document the development of SCC in a 58-year-old woman with an oral lesion diagnosed clinically as OLP and described histologically as having lichenoid features with dysplastic changes. The time from the initial diagnosis of oral lichenoid lesions to the patient’s return visit to the medical center with clinically evident cancer was three years and eight months. The SCC developed in the labial mucobuccal fold and left mandibular edentulous ridge, which had undergone multiple biopsy procedures.

Clinical Implications. This case does not provide answers to the ongoing controversy about the innate propensity of OLP to become malignant. However, in view of both the common occurrence of OLP and unresolved issues regarding its premalignant potential, this case report illustrates the need for histologic confirmation and close follow-up of patients with clinical lesions that have lichenoid features.

Eisenberg and Krutchkoff² suggested that some lesions diagnosed as lichen planus may have, in fact, been epithelial dysplasias with a clinical lichenoid appearance. In 1985, they applied the term "lichenoid dysplasia" to lesions that could be clinically mistaken for OLP but have histologic features of dysplasia.¹ They proposed that epithelial dysplasia with lichenoid features (that is, LD) is a distinct histopathologic entity with a true malignant predisposition.¹

They attributed the similarity in the clinical appearance of OLP and LD to the lichenoid inflammatory infiltrates elicited by a cell-mediated immune response to multiple antigens.^1,3,4 However, if the clinical diagnosis is not verified by histologic examination, or if the incipient dysplastic changes in the presence of lichenoid features are not recognized or are overlooked, a misdiagnosis could result.⁵ Eisenberg⁵ argued that this initial misdiagnosis could explain why a benign condition such as OLP is considered by some to be premalignant.

	CASE REPORT

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A 58-year-old woman came to the University Oral Medicine Service, University of Medicine & Dentistry of New Jersey, Newark, in 1999 for diagnostic evaluation and treatment of symptomatic oral erosions of three years’ duration in her lower jaw. Two years previously, she began to experience isolated oral erosions and ulcerations, which gradually progressed in size to encompass the majority of the mucosal tissues in her lower jaw. The lesions were associated with pain of sufficient intensity to reduce her food intake and interfere with her ability to speak and perform oral hygiene. She denied cutaneous, nasal, ocular or vaginal involvement.

Medical history. The patient’s medical history was significant for inactive hepatitis C and type 2 diabetes mellitus, for which she was receiving daily oral hypoglycemic agents. The patient had a 20-pack-year history of smoking but had quit four years before the oral evaluation. She denied any history of alcohol or recreational drug abuse and reported no allergies. Both of her parents had died of cancers of unknown type. A review of systems was noncontributory. Pharmacological agents used during the preceding two years to manage the lesions included chlorhexidine gluconate and nystatin oral rinses, clotrimazole troches and topical benzocaine, as well as prednisone for a presumptive diagnosis of erosive lichen planus. The treatments were ineffective.

An oral medicine clinician performed an intraoral examination, which revealed a thick, white adherent plaque covering the lower edentulous ridge, with symptomatic areas of erythema and erosion in the right and left buccal mucosae and lower anterior vestibule (Figure 1). In some areas, the clinician could wipe off the white plaques, leaving behind painful, erythematous areas.

View larger version (107K): [in this window] [in a new window]   Figure 1. Clinical presentation of the oral lesion reveals a thick, white plaque covering the lower edentulous ridge, and areas of erosion in the lower labial vestibule and buccal mucosae, with associated peripheral keratotic striae. The clinician could wipe off some of the white plaques, leaving behind painful erythematous areas.

Treatment. After consulting with the patient’s physician, we prescribed a short course of 50 milligrams of prednisone daily. Pain relief was provided with a 1:1:1 mixture of lidocaine, laxative/antacid (Phillips’ Milk of Magnesia, Bayer, Morristown, N.J.) and antidiarrheal (Kaopectate, Pfizer, New York). We educated the patient regarding denture hygiene. In addition, we prescribed nystatin suspension three to four times daily for two weeks to treat candidal superinfection.

Although the patient experienced some improvement, she continued to have significant white patches and oral erosions, which rendered her unable to chew and eat adequately. Because of her poor diabetic control, we discontinued the prednisone treatment three weeks later and instituted topical treatment with dexamethasone rinse and clobetasol ointment. During the next 16 months, in consultation with her physician, we treated residual lesions with other immunomodulating medications, including cyclosporine, mycophenolate mofetil and dapsone.

The patient’s symptoms and lesional appearance showed a general improvement with medical therapy; however, the continued presence of the lesions prompted a second biopsy. We sampled three sites on the lower edentulous ridge. Microscopic examination revealed, in addition to lichenoid mucositis and hyperkeratosis, varying degrees of mild-to-moderate epithelial dysplasia (Figure 2). Despite therapy with nystatin and clotrimazole during the preceding months, we noted Candida organisms on the surface of the specimens, complicating the symptoms and treatment of the oral lesions.

View larger version (147K): [in this window] [in a new window]   Figure 2. Lichenoid dysplasia. A section of the oral mucosa exhibits hyper-keratosis and an underlying bandlike lymphocytic infiltrate. Note the intact and hyperchromatic basal cell layer (hematoxylin-eosin stain, original magnification x10). Inset. Abnormal cellular maturation indicative of epithelial dysplasia (hematoxylin-eosin stain, original magnification x40).

Two and one-half years later, the patient returned to the oral medicine clinic complaining of pain and reporting a growth in her mouth. She had not pursued any treatment for the oral lesions since her last visit. The extraoral examination was significant for lymphadenopathy in the left posterior cervical chain. The intraoral examination revealed generalized white patches with areas of erosion and erythema on the left and right buccal mucosae, as well as on the floor of the mouth. In addition, we observed a 2 x 2-centimeter red-and-white indurated, exophytic mass in the lower left mucobuccal fold extending over the edentulous ridge (Figure 3).

View larger version (81K): [in this window] [in a new window]   Figure 3. Clinical presentation of the lesion two and one-half years after the patient’s last visit to the oral medicine clinic. An exophytic 2- x 2-centimeter growth with a white papillary surface was present on the lower left labial mucosa, extending to the alveolar ridge and floor of the mouth.

View larger version (161K): [in this window] [in a new window]   Figure 4. Squamous cell carcinoma. Microscopic examination revealed invasive islands of malignant squamous cells arising from dysplastic surface epithelium. The submucosa is crowded with epithelial nests exhibiting marked cytologic atypia (hematoxylin-eosin stain, original magnification x4).

	DISCUSSION

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Histologic features. The histologic features¹² of OLP consist of hyperkeratosis, epithelial atrophy with dissolution of the basal cell layer and epithelial ridges that may be blunted or may exhibit a sawtooth configuration. Occasional degenerating keratinocytes, known as colloid or Civatte bodies, may be seen near the interface between the epithelium and connective tissue. A population of T lymphocytes is distributed within the lamina propria in a linear fashion.

The microscopic pattern of OLP is nonpathognomonic and may be shared with such diseases as lichenoid drug eruptions, hypersensitivity reactions and lupus erythematosus, necessitating a correlation with the patient’s medical history and current physical condition.

LD designates the histologic combination of mucosal epithelial dysplasia and certain features of lichen planus, primarily the pattern of the inflammatory infiltrate.^1,12 It is not a variant or transitional form of lichen planus, but instead represents a distinct entity that has a true potential for malignant transformation. In addition to abnormal epithelial maturation and cytology, LD exhibits other histologic features that separate it from OLP.^1,12

The basal cell layer usually is intact, and the associated inflammatory infiltrate varies in intensity and cell population. Also, the contour of the epithelial ridges is rounded, in contrast to the jagged appearance seen in OLP. In addition, the clinical features of LD are more typical of preneoplastic lesions than of OLP.¹² Moreover, some experts believe that the bandlike mononuclear cell infiltrate in LD represents a cell-mediated immune response provoked by the oncogenic epithelial alteration, rather than by the surface of the essentially benign epithelial basal cells, as is the case with OLP.^1,4

Published case reports of OLP conversion to SCC have created considerable discussion, leading to a controversy surrounding the malignant potential of OLP.^12,13 Many studies^14–17 and case series¹⁸ have shown an association between the two diseases, with an incidence of cancer development ranging from 0.4 to 5.6 percent^14–17,19 within follow-up periods of up to 22 years.²⁰

Published case reports of oral lichen planus conversion to squamous cell carcinoma have led to controversy surrounding the malignant potential of oral lichen planus.

The impression of premalignancy is by no means universal,¹² however, and a recent literature review²⁰ has cast doubt on many of the reported cases of SCC arising in OLP, mainly because of poor documentation. In addition, Lovas and colleagues²¹ posited that some cases of presumed malignant transformation of OLP likely represent underdiagnosed cases of epithelial dysplasia, with a dense underlying inflammatory infiltrate (in other words, LD). Therefore, although some instances of malignant conversion have been adequately demonstrated, the true rate of this event probably is much lower than what has been estimated.

In this case, the patient initially came to us with lesions clinically resembling plaque-type OLP in the lower edentulous ridge, accompanied by atrophic and eroded areas in the buccal and labial vestibules. An incisional biopsy specimen of the left buccal mucosa exhibited many of the conventional features of lichen planus. However, atypical features also were present and consisted of mild nuclear enlargement and scattered mitotic figures within the spinous layer. This epithelial atypia within an overall lichenoid setting also was present in the mandibular ridge mucosa sampled nearly eight months later. We also noted candidal overgrowth.

Descriptive diagnosis. Because of the morphological departure of these specimens from classic lichen planus, we made a nonspecific descriptive diagnosis of lichenoid mucositis with mild-to-moderate epithelial dysplasia. We favored a descriptive diagnosis owing to the controversy within the oral pathology community surrounding the LD designation. The final biopsy specimens from this area exhibited a verrucous surface architecture with abundant surface parakeratin harboring numerous fungal pseudohyphae. The overlying epithelium exhibited an increase in atypia with the invasion of submucosa with cords of malignant cells. We also noted rudimentary keratin pearl formation.

Owing to the 2-year interruption in the patient’s follow-up, we were not able to pinpoint the exact time she developed SCC. However, the time from the initial diagnosis of the oral lichenoid lesions to her return visit to the oral medicine clinic with clinically evident cancer was approximately three years and eight months. The SCC developed in the labial mucobuccal fold and left mandibular edentulous ridge, which had undergone several biopsy procedures since her initial visit to our clinic.

It is difficult to discern the true nature of the process occurring in this patient. Did the dysplasia arise in the setting of pre-existing lichen planus in response to persistent candidal super-infection, or is this a case of de novo LD? A number of investigators have reported a high degree of malignant transformation in homogenous, plaquelike and reticular OLP lesions, advocating their close follow-up, particularly when they involve cancer-prone sites in patients with high-risk behavior (that is, smoking and drinking).^10,11,14

We do not know the reasons for possible malignant development in OLP lesions. Researchers have not found tobacco and alcohol exposure to be greater in patients with OLP compared with the general population.^22,23 Our patient reported a 20-pack-year history of smoking and had quit four years before her initial visit to our clinic. She denied any history of alcohol abuse. Infection by Candida albicans may be important in malignant transformation of OLP.¹⁵ This organism can form carcinogenic N-nitrosobenzylmethylamine²⁴ and has been linked with malignant changes in some leukoplakias.²⁵

Several researchers^26–28 have identified human papilloma virus, or HPV, which is considered a risk factor in oral carcinogenesis, in OLP lesions. Attempts to identify the presence of HPV in malignant tissue through DNA extraction and immunohistochemistry were unsuccessful in this case, thereby excluding this virus as a contributing factor in the development of the tumor. Immunosuppression increases the risk of certain types of malignancy.²⁹ We used multiple topical and systemic immunosuppressants, with particular effect on T-cell population, to treat the lesions in our patient. The role of these medications in the malignant transformation in this case remains unclear.

Biopsy-site selection is critical, because the histologic features may vary within lesions, and cytologically significant areas may be missed.

The uncertainty regarding the underlying process in our patient stems in part from a number of issues confounding the interpretation of oral lichenoid lesions. First is the lack of universally accepted diagnostic criteria for OLP.^30–32 While some clinicians rely on clinical features of OLP for diagnosis,^22,33,34 others use histologic criteria¹⁴ and yet others apply both clinical and microscopic features for diagnosis.^35,36 In addition, histologic interpretation of OLP is a somewhat subjective and insufficiently reproducible process.³⁷

Second is the lack of well-defined, objective clinical criteria for epithelial dysplasia,¹⁵ requiring a biopsy to verify the diagnosis of OLP except when classic, bilateral, lacelike lichenoid lesions are present on non–cancer-prone sites.^5,15 Third, atypical epithelial changes may be seen in benign reactive lesions³⁸ and do not always suggest a preneoplastic feature.³² In addition, more than one disease process could be present concurrently in a given patient.⁵

If multiple biopsies are not feasible, it is best to perform a biopsy of the lesion involving the cancer-prone location.⁵ Moreover, biopsy-site selection is critical, because the histologic features may vary within lesions, and cytologically significant areas may be missed. Ulcerated, indurated or exophytic areas are most likely to demonstrate dysplastic or malignant features, and therefore clinicians should choose them for sampling.

Close follow-up important. This case does not provide answers to the ongoing controversy about the premalignant potential of OLP. However, in view of both the common occurrence of OLP and unresolved issues regarding its premalignant potential, the need for close follow-up of lesions with clinical lichenoid features clearly is illustrated. Clinicians must classify the clinical form of OLP when planning the follow-up regimen.¹¹ Asymptomatic reticular OLP does not need active treatment, but may require only patient reassurance¹⁰ and periodic observation.

Regular follow-up is particularly important for patients with atrophic and erosive-type OLP.³² Clinicians should examine these patients two to four times a year and monitor them for any change in lesion appearance or symptoms.³² More frequent follow-up or additional biopsies may be needed if the clinical examination results indicate disease progression or suspicious lesional behavior.¹¹

At each follow-up visit, the clinician should perform a thorough clinical examination to identify any suspicious signs of malignant transformation.¹¹ He or she should identify any agents that may be causing lichenoid drug reactions, and, in consultation with the patient’s physician, recommend modifications in drug therapy in an attempt to treat these oral lichenoid lesions.

Koebner reaction, a common feature of lichen planus, refers to the development of lichenoid lesions in the areas exposed to irritation.³⁹ Therefore, professional oral hygiene procedures should be meticulous yet gentle to prevent tissue trauma and secondary occurrence of lichenoid lesions. Also, the clinician should identify and eliminate any possible local irritant such as defective dental restorations or a rough prosthesis to minimize frictional contact.¹⁰

The clinician should emphasize the need for appropriate home care regimens and monitor patient compliance. He or she should inform the patient about the disease characteristics, complicating factors and the need to cease tobacco and alcohol use.¹⁵ In addition, clinicians should educate patients regarding the possible risk of malignant transformation and the need for regular professional follow-up.¹⁵

	CONCLUSION

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Published case reports of OLP conversion to SCC have created a great deal of controversy about the true nature of oral lichenoid lesions. We have documented the development of SCC in a lesion diagnosed clinically as OLP and described histologically as having lichenoid features with dysplastic changes. This case raises many questions regarding the diagnostic process, illustrates the ongoing discussion regarding the premalignant potential of OLP and emphasizes the need for close follow-up of oral lichenoid lesions.

View larger version (120K): [in this window] [in a new window]   Dr. Fatahzadeh is an assistant professor, Division of Oral Medicine, Department of Diagnostic Sciences, University of Medicine & Dentistry of New Jersey—New Jersey Dental School, Room D-885, 110 Bergen St., Newark, N.J. 07103, e-mail "fatahza{at}umdnj.edu". Address reprint requests to Dr. Fatahzadeh.

View larger version (132K): [in this window] [in a new window]   Dr. Rinaggio is an assistant professor, Division of Oral Pathology, Department of Diagnostic Sciences, University of Medicine & Dentistry of New Jersey—New Jersey Dental School, Newark.

View larger version (121K): [in this window] [in a new window]   Dr. Chiodo is a resident, Department of Oral Surgery, University of Medicine & Dentistry of New Jersey—New Jersey Dental School, Newark.