Eosinophilic Ulcer of the Oral Mucosa: a Distinct Entity Or a Non-Specific
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Oral Diseases (2008) 14, 287–295. doi:10.1111/j.1601-0825.2008.01444.x Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Munksgaard All rights reserved http://www.blackwellmunksgaard.com HOT TOPIC Eosinophilic ulcer of the oral mucosa: a distinct entity or a non-specific reactive pattern? S Segura, RM Pujol Department of Dermatology, Hospital del Mar, Universitat Auto`noma de Barcelona, Barcelona, Spain Eosinophilic ulcer of the oral mucosa (EUOM) is an eosinophilic ulcer of the tongue or traumatic granuloma uncommon self-limited oral condition that clinically with stromal eosinophilia (TGSE). Clinically, it usually manifests as a solitary ulceration with elevated indurate manifests as a persistent oral ulcer, which clinically may borders affecting the tongue, buccal mucosa or lip. give rise to a broad differential diagnosis with sev- Microscopically, it is characterized by a polymorphic eral infectious, tumoral and autoimmune conditions inflammatory infiltrate with a prominent polymorpho- (Table 1). nuclear eosinophilic component extending deep into the Histologically, in some cases typical features such as submucosa, underlying muscle and salivary glands. Large dense polymorphic inflammatory infiltrate with abun- mononuclear cells probably corresponding to histiocytes, dant eosinophils extending into the underlying muscle myofibroblasts or activated lymphoid cells are also fre- may lead to the diagnosis; however, in other cases, the quently observed. The exact pathogenetic mechanisms presence of large atypical cells intermixed with the implicated in the development of EUOM are poorly inflammatory infiltrate may be difficult to interpret understood; however, the possibility that trauma may and special immunohistochemical stains and molecular play a role in its development has been often postulated. studies will be required. Further studies such as Since its original description, the possibility that EUOM microbiological cultures and serological tests can also could be either considered an individualized disorder or a be performed. As there is no specific hallmark of the non-specific reactive pattern secondary to several stimuli disease, the diagnosis of EUOM has to be an exclusive has been discussed. EOUM may show some overlapping one. In this article, we review clinical and histopath- features with some entities such as atypical histiocytic ological features and differential diagnosis of EUOM granuloma, mucosal angiolymphoid hyperplasia with and discuss its existence as a distinct disease. eosinophilia, and Kimura disease. The clinical and histo- pathological features and the differential diagnosis of History EUOM are reviewed and its existence as a distinct disease discussed. Eosinophilic ulcer of the oral mucosa was first described Oral Diseases (2008) 14, 287–295 in adults by Popoff in1956. Firsts reports in the 1960s included this process within the spectrum of granuloma Keywords: eosinophilic ulcer; oral mucosa; traumatic granu- faciale and some authors proposed the term Ôulcerated loma; stromal eosinophilia; CD30-positive lymphoprolipherative granuloma eosinophilicum diutinum of the tongue’ disorders (Hjorting-Hansen and Schmidt, 1961). In 1970, this lesion was proposed as a distinct entity by Shapiro (Shapiro and Juhlin, 1970). Since then, different names such as TGSE (Elzay, 1983; Hirshberg et al, 2006); Introduction traumatic eosinophilic granuloma of the tongue (Ficarra Eosinophilic ulcer of the oral mucosa (EUOM) is an et al, 1997; Alobeid et al, 2004) and eosinophilic ulcer of uncommon self-limited oral condition mostly appearing the tongue or the oral mucosa (Doyle et al, 1989; El- on the tongue. Several terms have been used to describe Mofty et al, 1993; Mezei et al, 1995; Velez et al, 1997; this process, such as traumatic granuloma of the tongue, Garcia et al, 2002) have been used to define this process leading to further confusion. An apparently different disorder had been previously Correspondence: S Segura, MD, Department of Dermatology, Hos- described in the pediatric age. Riga in 1881 reported an pital del Mar, Passeig Marı´tim 25–29, 08003, Barcelona, Spain. Tel: +34 93 2483380, Fax: +34 93 2483328, E-mail: ssegura@ ulcerative lesion in the ventral surface of the anterior imas.imim.esc tongue or in the vestibular mucosa of lower lip, in Received 25 January 2008; accepted 29 January 2008 children under the age of 2 years, produced by friction Eosinophilic ulcer of oral mucosa S Segura and RM Pujol 288 Table 1 Clinical differential diagnosis for oral ulcers similar to EUOM after experimentally producing re- peated injuries to the tongue. However, these results were Infections not confirmed by von Domarus et al (1980)after perform- Syphilis ing similar investigations. Other authors have suggested Herpes Tuberculosis that trauma is only a contributing factor in the develop- Histoplasmosis ment of EUOM and that probably some viral or toxic Tumors agents could be implicated (Tang et al, 1981). However, Squamous cell carcinoma different attempts have failed to demonstrate viral Histiocytosis X Lymphoma particles and⁄or ultrastructural dense immune deposits Salivary gland tumours in clear-cut cases of EUOM. Autoimmune diseases As most traumatic oral ulcers are devoid of eosin- Discoid lupus erythematosus ophils, several hypotheses have been proposed to Wegener’s granulomatosis explain the prominent eosinophilic infiltrates observed Others Major apthous ulcers in this lesion. A possible direct pathogenic role of Eosinophilic ulcer of the oral mucosa cytokine and chemotactic factors released by eosin- ophils in the development of EUOM has been hypoth- esized. A possible interaction between mast cell, a release between the tongue or lip and teeth. Histological eosinophil chemotactic factors and tissue eosinophilia features of this condition were described by Fede in has also been postulated. Elzay histologically compared 1890. It was most commonly called Riga–Fede disease, 41 cases of EUOM with 30 patients with a variety of but other synonyms were referred in the early literature, inflammatory conditions affecting the oral mucosa such as Riga’s disease, sublingual ulcer, sublingual (control group) and biopsies from normal oral mucosa granuloma, sublingual growth in children, and repara- (Elzay, 1983). In EUOM cases, in addition to stromal tive lesion of the tongue (Elzay, 1983). Rakocz et al eosinophilia, an increase in mast cells (intact and (1987) first associated this condition with familial degranulating) was observed. In all control tissues, dysautonomia. The absence of pain sensation leads to eosinophils were absent whereas a light to moderate oral self-inflicted lesions after the appearance of incisors population of mast cells was observed in normal and teeth. Thus, early recognition of this entity is important, inflamed oral tissue. An increased number of mast cells because it may be the presenting sign of an underlying in the peripheral underlying connective tissue were also neurological disorder in this population (Eichenfield detected by El-Mofty et al (1993). Conversely, Regezi et al, 1990; Zaenglein et al, 2002). et al (1993) found scarce numbers of mast cells in In 1983, Elzay revised 19 cases from literature of EUOM infiltrates, although a significant numbers were both traumatic eosinophilic granuloma and Riga-Fede detected in the normal surrounding tissue (Regezi et al, disease, reporting 41 new cases with clinical and 1993). Nevertheless, the exact role of mast cells in the histological descriptions. The authors proposed to pathogenesis of EUOM remains controversial. include both manifestations in one entity as they A traumatic disruption of the oral mucosa would shared distinct histological and clinical characteristics facilitate the action of a non-identified etiologic factor (Elzay, 1983). (microorganisms, toxins or foreign proteins) into the connective tissue. This etiologic factor, in a predisposed Etiopathogenic mechanisms subject, could induce an intense inflammatory reaction giving rise to a mast cell-eosinophil reaction similar to The pathogenic mechanisms implicated in the develop- that noted in the studies on bronchial asthma. A ment of EUOM are poorly understood and only a possible additional role of cytotoxic T cells causing limited number of studies have been specifically mucosal damage in EUOM has also been suggested. designed to elucidate the origin of this condition. Hirshberg et al, (2006) demonstrated the presence of Several clinical features and epidemiological data seem aggregates of TIA-1 positive cells, a marker of cyto- to suggest that trauma may play a role in the development toxic T cells in 12 cases of TGSE (Hirshberg et al, of this disorder: (i) A traumatic event is recorded in a 2006). Recent studies have shown that eosinophils may variable proportion of cases of EUOM ranging from 0 to also interact with fibroblasts and endothelial cells 100% of the cases (average 39%) (Bhaskar and Lilly, (Munitz and Levi-Schaffer, 2004). Their interaction 1964; Elzay, 1983; Doyle et al, 1989; El-Mofty et al, 1993; with fibroblasts may result in a contribution towards Garcia et al, 2002; Hirshberg et al, 2006); (ii) the lesions wound healing via the synthesis of transforming are frequently located on the tongue where traumatisms growth factor (TGF) a and b, as demonstrated in a are frequent, and (iii) two peaks of age incidence have study using a mice wound-healing model (Wong et al, been identified in EUOM, one peak during the first 1993). A lack of significant synthesis of transforming 2 years of life, in