Abstract

Esophageal lichen planus is an underrecognized condition, with fewer than 50 cases reported to date. Unlike cutaneous lichen planus, esophageal lichen planus occurs almost exclusively in middle-aged or older women who also have oral involvement. It commonly involves the proximal esophagus and manifests as progressive dysphagia and odynophagia. Endoscopic findings can include lacy white papules, pinpoint erosions, desquamation, pseudomembranes, and stenosis. Histologic features of esophageal lichen planus have only rarely been illustrated. They differ from those of cutaneous disease in several respects, including the presence of parakeratosis, epithelial atrophy, and lack of hypergranulosis. Correct diagnosis of esophageal lichen planus is difficult but bears important therapeutic implications. It is typically a chronic and relapsing condition that can require systemic or local immunosuppressive therapy and repeated endoscopic dilatations for esophageal strictures. Esophageal lichen planus may have malignant potential, as evidenced by 3 patients who developed squamous carcinoma of the esophagus after longstanding disease.

Lichen planus is a subacute to chronic inflammatory disease affecting the skin, mucous membranes, nails, and hair.1 Its precise cause is unknown, and several theories about infectious (viral), neurologic, genetic, and immunologic factors have been proposed.2 However, lichen planus appears to be mediated by cytotoxic CD8+ T cells that attack an antigen in the basal epithelium in a manner resembling graft-versus-host disease.3 Uncommon locations of lichen planus include the conjunctivae, pharynx, esophagus, stomach, rectum, anus, and bladder. Involvement of the esophagus was first described by Al-Shihabi and Jackson in 1982.4 Since that time, only approximately 40 cases have been documented in the English language literature,5 and the histologic features of esophageal lichen planus have only rarely been illustrated.4,6–8 As a result, esophageal involvement by lichen planus is not well recognized by either pathologists or gastroenterologists. Patients' symptoms are often attributed to gastroesophageal reflux, despite histologic examination of involved tissue.8–10 The resulting delay in diagnosis allows for continued esophageal inflammation and persistent dysphagia,7–9 the possibility of esophageal stenosis, and a risk for the development of esophageal squamous cell carcinoma (a rare manifestation).10–13 The objective of this review is to increase familiarity with esophageal lichen planus, its clinical and endoscopic findings, and its histopathologic features.

CLINICAL FEATURES

Lichen planus of the skin affects both genders with equal frequency, with most patients comprising middle-aged adults. Clinically, it is characterized by eruptions of violaceous, scaling pruritis and plaques. In contrast to cutaneous lichen planus, esophageal lichen planus has been reported almost exclusively in middle-aged to older women. Esophageal lichen planus is poorly associated with cutaneous disease, but it is strongly associated with oral involvement. Oral lichen planus has been present in nearly all reported patients, although occasionally the oral involvement has been noted subsequent to the diagnosis of esophageal lichen planus,4,6,8–10 and there has been one report of esophageal lichen planus in a patient without any oral, cutaneous, or genital lesions.14 

The prevalence of esophageal lichen planus among patients with oral lichen planus is unknown. In one study of 19 patients with mucocutaneous lichen planus, upper endoscopy revealed esophageal lesions in 5 (26%), although only 1 of these patients had symptomatic dysphagia, and the endoscopic findings in the other 4 cases were quite subtle.15 Another study suggested a much lower rate of esophageal involvement in this population. Eisen16 retrospectively studied 584 patients with oral lichen planus and found 8 patients who underwent endoscopy because of dysphagia; only 4 of these had both endoscopic and histologic findings consistent with esophageal lichen planus, suggesting a prevalence of less than 1%. The true prevalence of esophageal lichen planus in the general population is nearly impossible to determine, for several reasons: clinical and pathologic unfamiliarity with the condition, the high rate of asymptomatic or subtle disease, and the possibility that esophageal involvement could be the sole manifestation of lichen planus.17 

Although patients with esophageal lichen planus can be asymptomatic, the typical clinical manifestations include dysphagia and odynophagia.15 In a Mayo Clinic (Rochester, Minn) study of 6 patients diagnosed with esophageal lichen planus, all presented with dysphagia, and 2 had odynophagia.18 Reflux-type symptoms are uncommon.17 Endoscopic findings are quite peculiar but can be subtle and include elevated lacy white papules, esophageal webs, pseudomembranes, desquamation, and superficial pinpoint erosions with and without stenosis.7,9,15 In the Mayo Clinic study, 4 patients (67%) had strictures, and all were located in the cervical esophagus.18 The proximal or midesophagus is the most common location for all esophageal lesions in lichen planus (and should serve as a diagnostic clue that the lesions are not reflux related). However, the entire esophagus can also be affected, with sparing of the gastroesophageal junction.17 

The precise etiology and pathogenesis of oral lichen planus is unknown. However, it is well documented that the disease represents a cell-mediated immune response.19 It has been suggested that in lichen planus there is an immune response to an exogenous or endogenous antigen found in the basal keratinocytes which activates the Langerhans cells, which then present the antigen to CD4-positive T lymphocytes that go to the oral mucosa lamina propria through activation of adhesion molecules. Keratinocytes respond to the injury by producing cytokines that promote CD8-positive T-lymphocyte stimulation. These CD8-positive cytotoxic cells are then distributed near the epithelium in order to destroy it.20 Several predisposing factors have been implicated in the pathogenesis of oral lichen planus, including systemic medications such as antimalarial drugs, nonsteroidal anti-inflammatory drugs, antihypertensive agents, and dental materials such as amalgam. Genetic background also seems to play a role, as several familial cases have been reported.21 The association between oral lichen planus and chronic liver disease is controversial, and several studies have been performed regarding its association with chronic hepatitis C. Many reports have suggested the association of lichen planus and hepatitis C infection, and the prevalence of this association varies from 0% to 62%, with conflicting results.22 Finally, oral lichenoid lesions are part of the spectrum of chronic graft-versus-host disease that occurs after allogenic bone marrow transplantation. Despite their different antigen specificity, it is likely that they share similar immunologic effector mechanisms.3,21 Although there have been no detailed studies published specifically addressing the pathogenesis of esophageal lichen planus, we speculate that it would be similar to that of oral lichen planus.

HISTOPATHOLOGIC FEATURES

The histologic features of esophageal lichen planus differ from those in the skin. Cutaneous lichen planus is typically characterized by hypergranulosis, hyperkeratosis, acanthosis, and “saw-tooth” elongation of the rete pegs.23 In comparison, the esophageal epithelium, which normally lacks orthokeratosis or a granular layer, usually shows parakeratosis rather than orthohyperkeratosis and frequently lacks hypergranulosis (Figure, A). In addition, the esophageal epithelium may be atrophic rather than acanthotic, or it can show variable thinning and acanthosis. The histologic features of esophageal lichen planus, therefore, more closely resemble those seen in oral rather than cutaneous disease.24 The most characteristic finding in esophageal lichen planus is a bandlike or lichenoid lymphocytic infiltrate involving the superficial lamina propria and basal epithelium (Figure, B). A predominance of mature T cells is present within the infiltrate, and these are associated with basal keratinocyte degeneration, often including characteristic Civatte bodies (which are necrotic keratinocytes with anucleate remnants) (Figure, C and D).11,17 Concomitant Candidal colonization in affected areas of the esophagus has been observed in 2 cases.3,25 

A, Esophageal squamous epithelium showing parakeratosis and lymphocytic infiltrate with scattered Civatte bodies (hematoxylin-eosin, original magnification ×100). B, A bandlike or lichenoid lymphocytic infiltrate involving the superficial lamina propria and basal epithelium (hematoxylin-eosin, original magnification ×200). C and D, Esophageal squamous epithelium showing lymphocytic infiltrate predominantly involving the basal layer and multiple Civatte bodies (hematoxylin-eosin, original magnifications ×100 [C] and ×200 [D])

A, Esophageal squamous epithelium showing parakeratosis and lymphocytic infiltrate with scattered Civatte bodies (hematoxylin-eosin, original magnification ×100). B, A bandlike or lichenoid lymphocytic infiltrate involving the superficial lamina propria and basal epithelium (hematoxylin-eosin, original magnification ×200). C and D, Esophageal squamous epithelium showing lymphocytic infiltrate predominantly involving the basal layer and multiple Civatte bodies (hematoxylin-eosin, original magnifications ×100 [C] and ×200 [D])

Lymphocytic infiltration of the esophageal mucosa in itself is not pathognomonic for esophageal lichen planus. Hence, performing immunostains for lymphocytes (specifically T cells, such as CD3, CD4, and CD8) would not be helpful in differentiating esophageal lichen planus from other pathologic conditions in the differential diagnosis. Medications such as gold, thiazides, and antimalarials can induce lichen planus–like lesions and need to be excluded clinically.24 Esophageal mucosa adjacent to ulcer sites secondary to infectious or pill-induced esophagitis can also show nonspecific lymphocytic infiltrates. Infectious agents, such as herpes simplex or cytomegalovirus, are usually easily excluded on biopsy material, but exclusion of esophagitis resulting from pill ingestion or caustic substances requires clinical correlation. In addition, lymphocytic infiltrates are occasionally prominent, although often focal, in patients with gastroesophageal reflux. However, the other histologic criteria for gastroesophageal reflux disease, including intraepithelial eosinophils, are usually absent in esophageal lichen planus. Moreover, lichen planus typically involves the upper or midesophagus, which would be unusual in gastroesophageal reflux. Finally, patients with esophageal lichen planus do not respond to medications for reflux disease, such as proton pump inhibitors.18 

TREATMENT AND PROGNOSIS

Therapeutic options include systemic corticosteroids, retinoids, cyclosporine, and azathioprine. Most patients reported in the literature have shown clinical improvement with one or more of these agents, but relapse can be expected when treatment is discontinued.4,6–8,10 The natural course of esophageal lichen planus is not well studied, and it is unknown whether spontaneous clearing of esophageal lesions can occur, as seen in a significant number of patients with cutaneous lichen planus. Most patients appear to have a chronic, relapsing course. In many cases, multiple endoscopic dilatations are required for symptomatic relief of recurring esophageal strictures. A recent article describes improvement in esophageal inflammation, less dysphagia, and need for fewer dilatations among 3 patients with lichen planus who were treated with intralesional corticosteroid injections and/or oral tacrolimus.3 

An increase in squamous cell carcinomas among patients with cutaneous and mucosal lichen planus has long been assumed, although this has only been proved in the case of oral lichen planus. A large epidemiologic study from Sweden reported on 2071 patients who were followed for an average of 9.9 years after their diagnosis of lichen planus and confirmed a definite risk for oral carcinoma, elevated 5.9-fold compared with the general population.26 It was long expected that esophageal lichen planus would, by analogy, also carry an increased risk for esophageal squamous carcinoma, but only recently have cases been reported. In 2003, Calabrese and colleagues12 described a middle-aged woman who developed squamous carcinoma of the proximal esophagus nearly 10 years after her initial diagnosis of esophageal lichen planus at age 49. Interestingly, there was high-grade squamous dysplasia in nearby epithelium, but neither the dysplasia nor the carcinoma had been detected prior to the development of an unresectable mass lesion, despite the fact that the patient had undergone periodic surveillance endoscopies and biopsies.12 Two additional patients with squamous cell carcinoma in the setting of longstanding dysphagia due to esophageal lichen planus were reported in 2006, one with an extensive area of high-grade squamous dysplasia extending for 10 cm in the proximal to midesophagus.13 It was hypothesized that the premalignant potential of oral and esophageal lichen planus could relate to increased turnover of basal epithelial cells as well as decreased immune surveillance in the setting of immunosuppressive therapy.12 These cases suggest a chronic inflammation—dysplasia—carcinoma pathway in esophageal lichen planus that could potentially be amenable to surveillance, possibly aided by use of high-magnification chromoendoscopy.13 However, there are currently no screening or surveillance recommendations for affected patients. Dilatation of esophageal strictures that are wrongly presumed to be peptic in origin, without accompanying medical treatment directed at the lichen planus, can sometimes exacerbate extraesophageal lichen planus lesions in a Koebner-like phenomenon (Koebner-like phenomenon is the development of isomorphic pathologic lesions in the traumatized uninvolved skin/mucosa of patients who have cutaneous disease).7,9,10,27 

CONCLUSIONS

The interpretation of biopsy specimens of esophageal lichen planus by pathologists is difficult and is not aided by the rarity of the condition. However, esophageal lichen planus should be suspected when the following are present: (1) occurrence in a middle-aged to older women; (2) presence of other erosive mucosal lesions; (3) involvement of the proximal esophagus; and (4) histologic finding of a bandlike or lichenoid lymphoid infiltrate involving the superficial lamina propria and basal epithelium, with presence of Civatte bodies. Recognition of esophageal lichen planus is important for several reasons. Misinterpretation of the histologic features as secondary to reflux disease or as simply a nonspecific reaction can lead to delay in the diagnosis and continuation or worsening of symptoms.7–10 Recently, a few cases of invasive squamous cell carcinoma have been described to develop in the setting of esophageal lichen planus and have suggested a dysplasia-carcinoma sequence.12,13 However, the role of endoscopic surveillance to detect early dysplasia in patients diagnosed with esophageal lichen planus remains to be established in future studies.

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The authors have no relevant financial interest in the products or companies described in this article.

Author notes

Reprints: Vishal S. Chandan, MD, Department of Pathology, Hilton 11, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (chandan.vishal@mayo.edu)