How to cite this article: Esquivel-Pedraza L, Fernández-Cuevas L, Ruelas-Villavicencio AL, Guerrero-Ramos B, Hernández-Salazar A, Milke-García MP, Méndez-Flores S. [Oral squamous cell carcinoma and lichen planus vs. lichenoid lesions. Case report]. Rev Med Inst Mex Seg Soc 2016;54(5):673-9.
Received: March 11th 2015
Accepted: June 16th 2015
Lilly Esquivel-Pedraza,a Laura Fernández-Cuevas,b Ana Lilia Ruelas-Villavicencio,a Brenda Guerrero-Ramos,a Amparo Hernández-Salazar,a María del Pilar Milke-García,c Silvia Méndez-Floresa
aDepartamento de Dermatología, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”
bDepartamento de Patología Bucal, Centro Dermatológico “Dr. Ladislao de la Pascua”
cDivisión de Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”
Secretaría de Salud, Ciudad de México, México
Communication with: Lilly Esquivel-Pedraza
Telephone: (55) 5487 0900, extensiones 2435 y 2419
Background: The development of squamous cell carcinoma from oral lichen planus is controversial. We report a case of intraoral squamous cell carcinoma, which presents together with lesions of oral lichen planus. The aim of this report was to analyze the problem to distinguish between the incipient changes of squamous cell carcinoma from the features described in oral lichen planus, in order to establish an accurate diagnosis of both entities.
Clinical case: A 57-year old man with a history of smoking and chronic alcohol intake, who had an ulcerated tumor mass located in the tongue, and bilateral white reticular patches on oral mucosa and borders of the tongue. The histopathological report was moderately differentiated invasive squamous cell carcinoma and lichen planus respectively.
Conclusions: The premalignant nature of OLP is still indeterminate and controversial, this is primarily due to inconsistency in the clinical and histological diagnostic criteria used to differentiate cases of oral lichen planus from lichenoid reactions or other lesions causing intraepithelial dysplasia with high potentially malignant transformation. Oral lichenoid reactions are possibly most likely to develop malignant transformation as compared to the classic OLP lesions.
Keywords: Squamous cell carcinoma; Mouth neoplasms; Lichen planus
Lichen planus (LP) is a relatively common inflammatory disease affecting skin, skin appendages, and/or oral mucosa or others. About 1.4-3.2% of the population can develop LP. The prevalence of oral LP (OLP) is estimated at 2%.1 Its etiology remains unknown, suggesting a T cell-mediated autoimmune pathogenesis, in which cytotoxic T lymphocytes induce apoptosis of epithelial cells. The disease is characterized by chronic inflammation with infiltration of T lymphocytes to subepithelial or subepidermal mucosa and skin, respectively.
Clinically, OLP can manifest in various ways: white plaque, reticulated, atrophic or erosive, pigmented, papular, and bullous.2 The reticular variant is the most common, appearing as white plaques consisting of a series of slightly elevated lines, that when intertwined acquire the characteristic pattern of lace. It may also look ring-like with fine grooves radiating from the periphery to the outside of the lesion. It is located mainly in the vestibular mucosa, and approximately 10% of cases of OLP occur only in the mucosa of the gingiva and are usually asymptomatic. By contrast, in the atrophic, erosive, and bullous forms of OLP, the symptoms are frequent and of varying intensity. Erosive LP is the most aggressive presentation of the disease, and is usually painful. This variant is characterized by superficial erythematous, erosive, or plainly ulcerative areas, located predominantly in the oral mucosa, lingual dorsa, and gingival mucosa, the latter commonly referred to as desquamative gingivitis. Its association with HCV and diabetes mellitus has been described.3,4
The differential diagnosis of OLP includes a variety of lesions such as frictional keratosis, the chronic hyperplastic variant of candidosis, hairy leukoplakia, idiopathic or smoking-related leukoplakia, lichenoid reactions from various causes, lupus erythematosus, graft-versus-host disease, pemphigus vulgaris, pemphigoid, deficiency diseases, or recurrent canker sores, among others.3,4
The first case of squamous cell carcinoma (SCC) concomitant with OLP was described in 1910;5 since then, some studies6 and isolated cases7 about this relationship have been described.
It has been observed that patients with OLP may present oral SCC more often than the general population,6 primarily affecting females and involving the areas of the oral mucosa.8 Some researchers have determined its annual rate of malignant transformation, ranging between 0.04-4.9%,9,10 and have described a risk of developing SCC in OLP lesions in reticular lamina of 33%, in homogeneous plaque in 29%, atrophic in 13%, and ulcerative-erosive in 25%; however, recent research contradicts the above, finding that the plaque variant has been overrepresented among these studies.9,11 Contrary to the estimates made of the malignant potential of OLP, it is known that the frequency of OLP is variable in different parts of the world,12 making it difficult to establish actual figures for oral SCC associated with OLP, when data on OLP prevalence in most populations worldwide are presumed or unknown.
It has also been reported that in the general population, the incidence of oral SCC in patients with OLP is not very different from that observed in baseline studies. On the contrary, it has been estimated that if about 1-5% of OLP develop malignantly, OLP therefore should be the main source of oral cancer in many countries of the world;13 however, it has been observed that it is not, and some authors have even detailed that this is unlikely.14 In addition, reports in which the rate of malignant transformation of OLP has been estimated for various reasons do not correspond to the actual prevalence data; the main reason is because the calculations in most related studies have been conducted in cohorts of subjects with OLP from specialized centers for oral diseases; therefore, there are important biases in the benchmark estimates of published figures, and for the symptomatic type of OLP, as well as detection, care, and management biases, among others.
We present the case of a patient with lesions that share the diagnostic criteria for OLP and the simultaneous presence of oral SCC, in order to illustrate, analyze, and discuss the synchronicity of these entities and emphasize the difficulty of diagnosis, according to both clinical and current histopathological parameters.
Male patient of 57 years of age, who presented an asymptomatic lesion on the tongue, a month of evolution, detected by the patient after trauma and previously handled by doctors with antibiotics (ciprofloxacin), topical antiseptics (povidone-iodine), and prednisone (20 mg/day) without improvement. The patient has a history of heavy alcohol use over 20 years and smoking 40 cigarettes/day for 12 years, suspended 6 years ago (tobacco use index 24). Laboratory tests of peripheral blood, blood count, and blood chemistry showed no abnormalities except glycated hemoglobin levels.7,6
Physical examination found moderate xerostomia, with presence of white reticular bilateral plaques on the oral mucosa and side, edges, and body of the tongue (Figures 1 and 2), soft palate and anterior pillars; with generalized erythema of mucosa exacerbated in the middle dorsal third of the tongue, in association with erythematous candidosis. In addition, an ulcerated tumor lesion (Figure 3) with millimetric yellowish-white mottling, infiltrated and indurated, painful on palpation, in the left lateral edge of the tongue, extending to the tongue body, without lymphadenopathy. Two biopsies were taken; one with diagnostic impression of lichen planus versus lichenoid lesions of the right oral mucosa, and another as squamous cell carcinoma of the left side edge of the tongue. Topical antifungal (clotrimazole) was administered for 15 days, with the disappearance of the reticular lesions.
Figure 1 White reticular plaques affecting the right vestibular mucosa, characteristic of oral lichen planus
Figure 2 White reticular plaques in the tongue body and mouth floor, right side, compatible with oral lichen planus
Figure 3 Ulcerated tumor lesion infiltrated and indurated in lingual left edge, corresponding to squamous cell carcinoma
Microscopic study showed histologic features of lichen planus (Figure 4) of the sample taken from the vestibule, with hyphae of the fungus Candida sp, and the presence of moderately differentiated invasive SCC of the nodular lesion in the region of the left lingual edge (Figure 5). With these findings, the patient was referred to oncology for management.
Figure 4 Histologic image of oral mucosa lesion, showing liquefaction of the basal layer and intense underlying lymphocytic infiltrate, corresponding to lichen planus. (H & E, 40x)
Figure 5 Micrograph showing invasive squamous cell carcinoma. (H & E, 40x)
Isolated reports of patients with synchronic OLP and oral SCC have suggested the possibility of malignant transformation of OLP, so the World Health Organization (WHO) has classified it as a "potentially malignant condition". However, the premalignant character attributed to OLP has been the subject of constant controversy,15,16 particularly because it was held that its link to cancer is, in practice, almost nonexistent, which strongly suggests the possibility of a wrong initial diagnosis of OLP in the cases describing its transformation into SCC.
Various studies have been developed with the aim of assessing the malignant potential of OLP, considering that the diagnosis of LP is complex when it affects only the oral mucosa. The clinical and histological criteria for identification established by WHO is unclear, insufficient, and consequently unsatisfactory.17 From the clinical point of view it should be considered that there is a wide range of oral lesions that share morphological characteristics with OLP, and they impede distinction. In recent years, experts in oral pathology have tried to solve this issue through the establishment of clinical and histological criteria, which must be strictly met to establish the diagnosis of "real" OLP or as close as possible, and which can also be applied in research.18
According to the clinical criteria suggested recently to support the diagnosis of LP, oral lesions should be overwhelmingly bilateral and symmetrical, consisting of slightly raised whitish and anastomosing lines, forming a net pattern. These reticulated pattern features must always be present, even in the other morphological types of OLP, to be considered as such.5 However, these criteria are inadequate for not considering other clinical patterns of OLP when reticular lesions are absent; consequently, some clinical presentations may be excluded from the diagnosis of OLP, while being true OLP. In addition, clinical criteria for OLP are based only on the physical appearance of the lesions and, therefore, other injuries with the same clinical picture can be included in the diagnosis of OLP, without really corresponding to OLP. Moreover, these criteria also do not take into account the different causal agents that can also lead to lesions of the oral mucosa with an image of bilateral reticular white plaques, resembling OLP.
It is widely known that the characteristic clinical findings of OLP, such as reticular white striations and/or white papules, an essential feature of this disease, and the atrophic, ulcerative and/or bullous plaque variants, may be present at diagnosis or may occur during the course of the disease.19 But none of these clinical findings are unique or limited to OLP; on the contrary, a large number of lesions of the oral mucosa occur with the same clinical picture as OLP, as part of their presentation at some point during a disease or from specific conditions of the oral environment in certain patients. Consequently, these clinical features defined for OLP are not useful enough to categorically distinguish it from other diseases. Some specialists have even tried to validate the clinical and histological criterion or criteria of OLP through its practical application in blinded studies, without so far achieving success in distinguishing it from other reticulated lesions. Therefore, the current clinical and histological criteria are seen as particularly important tools to help us group patients that meet a defined diagnostic criteria, but are still inadequate to radically establish the diagnosis of OLP.20,21
Some authors have argued that cases of OLP that developed cancer, were not really OLP, but rather dysplastic lesions with lichenoid clinical findings. The implication of this premise is that patients with lichenoid dysplasia represent a different risk group, which can be identified with the appropriate use of available diagnostic methods for specialists in the area and, as such, should be distinguished from patients with OLP unrelated to dysplasia. The term lichenoid is used to refer to lesions that typically show clinical features, but do not fulfill histological criteria, or vice versa. The term "compatible" with OLP refers to lesions that partially meet both clinical and histological criteria.5 Therefore, today OLP diagnosis and its differentiation from lichenoid lesions remain difficult and controversial.
Some clinicians have established that LP has an unequivocal malignant potential with unspecified risk; but others mention that OLP and lichenoid lesions have a characteristic clinical and histological appearance, but not pathognomonic, which usually allows, in both cases, distinction from oral leukoplakia. However, the plaque type of lichen planus can often clinically resemble leukoplakia. There are also difficulties in distinguishing clinically between lichen planus and some lichenoid lesions (or by contact, etc.), which emphasizes the importance of biopsy in diagnosis.
Some studies have also tried to formulate histological criterion or criteria to establish the diagnosis of OLP with specialists in oral pathology blinded to the physical clinical image during visualization of the histological image, so far also without success in correlating OLP lesions, both histologically and clinically.22,23 Unlike cutaneous LP whose diagnosis is usually established based on the morphological characteristics of the lesions, in OLP the microscopic examination of tissue is essential to identify the required histological criteria.24 These include, among others, lymphocytic infiltrate with subepithelial band patterns, i.e., limited to the papillary and reticular surface layers of the lamina propria of the mucosa, with liquefaction of the basal layer of epithelium. Because of the possibility of malignancy, the presence of epithelial dysplasia histologically rules out the diagnosis of OLP, even if the observed epithelial cell changes are secondary to the inflammatory process and not from malignant transformation.25 But again, these histological features can also be shared with various disorders. Despite the aforementioned shortcomings, the definitive diagnosis of OLP is established only if both the clinical and histological parameters are fully met.
Biopsy is obviously an important tool in the OLP diagnostic process, but a diagnosis of OLP based solely on histopathology often leads to erroneous results. Moreover, the pathologist misinterpreting the microscopic study of a tissue sample from the oral mucosa can also often be a source of error,25 even if there is no adequate clinical correlation. A common mistake among physicians inexperienced in oral diseases is related to the selection of the tissue sample that is most representative of the characteristics of OLP; this is one of the important reasons why specialists should observe both the clinical picture of the patient and the histopathology, as much as possible. In some cases, as in lichenoid lesions from contact caused by restorative metal components, it may be virtually impossible to distinguish histologically from OLP.26 Such lesions can be distinguished based on other clinical parameters27 and not exclusively on the physical image; whereas lichenoid lesions are not widely known for their malignant transformation, their inclusion in OLP studies could be causing incorrect figures on the rate of malignant potential of OLP.28
Moreover, follow-up studies have recently been conducted and reported for cases not satisfactorily meeting the current diagnostic criteria of OLP, categorizing them as "lichenoid" lesions, distinguishing them from those that do meet all the criteria of OLP, observing that malignant transformation occurred exclusively in lichenoids and not in OLP, calculating a malignant transformation rate of 0.65% per year for lichenoid lesions, with a 219-fold risk.9 The rigorous application of clinical and histological criteria in these studies allowed for large differences between the so-called "lichenoid" lesions and those considered "lichen planus".5
Moreover, the coexistence of OLP and the presence of factors that predispose to oral cancer like smoking and alcoholism are elements to consider as variables that can directly affect the oral mucosa and make it susceptible to the development of a premalignant lesion, regardless of OLP lesions. The evaluation of the influence of other factors associated with the development of oral cancer on oral mucosa in patients with OLP has not yet been analyzed deeply.
Moreover, the presence of factors potentially causing the development of clinical and histological images of OLP not been described widely. The white lesions in bilateral reticular plaques observed in our patient are fully consistent with the clinical and histological characteristics of OLP according to new clinical definitions proposed in recent years. However, the subject also had erythematous candidosis of long evolution, probably more closely associated with xerostomia secondary to his intense smoking habit. In this case, by the strictly clinical definition of OLP, one cannot distinguish between the possibility of lichenoid lesions related to this mycosis, which presents similar clinical characteristics to OLP, demonstrating with this case one of the shortcomings in the clinical criteria. The reticulation of the oral mucosa in patients with similar characteristics and background usually disappears after antifungal management; therefore, in future consensus it would be advisable to consider including etiological criteria in both the diagnosis of OLP, and lichenoid lesions.
Therefore, the development of oral cancer observed in cohorts in which OLP has been diagnosed based on various criteria is doubtful. Also bear in mind that in most cases associated with SCC, OLP diagnosis has not been made by experts in oral pathology, or with well-defined criteria.
Moreover, an important factor to be considered in follow-up studies on the development of oral cancer in OLP, is the continuous and prolonged use of topical or systemic immunosuppressive drugs used in its management that could influence per se in the development of this malignancy, regardless of LP or in synergy.
In our case, the patient had the factors most commonly associated with the development of oral SCC, intense tobacco and alcohol use; immunomodulatory therapy with no improvement of reticulation, which disappeared after antifungal administration. In our patient, the histological sample of the areas that clinically corresponded to OLP, met the microscopic requirements to be considered LP. However, the presence of the fungus Candida sp was also evident, suggesting that the reticulated plaque was a secondary manifestation of candidosis more than a product of OLP, disappearing with antifungal management. Again, deficiencies in the histological criteria are demonstrated in this case.
Studies on the malignant potential of OLP have been distinguished by inconsistencies in the diagnostic criteria specifically used to establish LP, due to deficiencies in the approach taken to identify a true case of malignant transformation in OLP, by excluding other risk factors for malignant transformation and the absence of optimal management of patients to ensure the early diagnosis of malignancy. The consensus remains elusive, recently leading researchers in this field to publish conflicting work on the malignant potential of OLP and questions about advising the exclusion of patients with epithelial dysplasia or the consideration of a smoking habit on studies on LP and its malignant potential.11
The premalignant nature of OLP is still controversial and discussed. The controversy over the malignant potential of OLP is largely based on its intraoral definition.19 The initial problem arises from the question about what the strict definition is that fits OLP, and therefore what may be called true OLP.16,19,29 It has been maintained that OLP carries a very small but significant risk of developing oral cancer. That some patients with OLP can develop SCC is not impossible, but it is extremely rare; even with the higher estimate of the figures, you run the risk of causing unnecessary concern to patients with LP, and, on the other hand, saturating oncologists with lesions that do not concern them. The misdiagnosis of LP may also have influenced this perception.30 Oral lichenoid reactions may be lesions more likely to form the basis of malignant transformation, when compared to classic OLP, so it is recommended to have these injuries evaluated by professionals with extensive experience in the diagnosis of oral diseases, considering that there oral lesions that, despite not corresponding to real OLP, share clinical and histological features with this entity. For now, the council lies in carrying out biannual monitoring tests with experts in the field, particularly important in patients with lichenoid lesions.
The case presented in this paper shares clinical and histological characteristics of oral lichen planus according to the standard definition that prevails today, but it presents factors not considered in the definition that should rule it out, and reflects the need to establish stricter diagnostic criteria, favoring the distinction between lichen planus and lichenoid lesions in the mouth.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.