You are on page 1of 9

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 uncommon self-limited oral condition that clinically manifests as a solitary ulceration with elevated indurate borders affecting the tongue, buccal mucosa or lip. Microscopically, it is characterized by a polymorphic inflammatory infiltrate with a prominent polymorphonuclear eosinophilic component extending deep into the submucosa, underlying muscle and salivary glands. Large mononuclear cells probably corresponding to histiocytes, myofibroblasts or activated lymphoid cells are also frequently observed. The exact pathogenetic mechanisms implicated in the development of EUOM are poorly understood; however, the possibility that trauma may play a role in its development has been often postulated. Since its original description, the possibility that EUOM could be either considered an individualized disorder or a non-specific reactive pattern secondary to several stimuli has been discussed. EOUM may show some overlapping features with some entities such as atypical histiocytic granuloma, mucosal angiolymphoid hyperplasia with eosinophilia, and Kimura disease. The clinical and histopathological features and the differential diagnosis of EUOM are reviewed and its existence as a distinct disease discussed. Oral Diseases (2008) 14, 287–295 Keywords: eosinophilic ulcer; oral mucosa; traumatic granuloma; stromal eosinophilia; CD30-positive lymphoprolipherative disorders

eosinophilic ulcer of the tongue or traumatic granuloma with stromal eosinophilia (TGSE). Clinically, it usually manifests as a persistent oral ulcer, which clinically may give rise to a broad differential diagnosis with several infectious, tumoral and autoimmune conditions (Table 1). Histologically, in some cases typical features such as dense polymorphic inflammatory infiltrate with abundant eosinophils extending into the underlying muscle may lead to the diagnosis; however, in other cases, the presence of large atypical cells intermixed with the inflammatory infiltrate may be difficult to interpret and special immunohistochemical stains and molecular studies will be required. Further studies such as microbiological cultures and serological tests can also be performed. As there is no specific hallmark of the disease, the diagnosis of EUOM has to be an exclusive one. In this article, we review clinical and histopathological features and differential diagnosis of EUOM and discuss its existence as a distinct disease.

History
Eosinophilic ulcer of the oral mucosa was first described in adults by Popoff in1956. Firsts reports in the 1960s included this process within the spectrum of granuloma faciale and some authors proposed the term Ôulcerated granuloma eosinophilicum diutinum of the tongue’ (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); traumatic eosinophilic granuloma of the tongue (Ficarra et al, 1997; Alobeid et al, 2004) and eosinophilic ulcer of the tongue or the oral mucosa (Doyle et al, 1989; ElMofty et al, 1993; Mezei et al, 1995; Velez et al, 1997; Garcia et al, 2002) have been used to define this process leading to further confusion. An apparently different disorder had been previously described in the pediatric age. Riga in 1881 reported an ulcerative lesion in the ventral surface of the anterior tongue or in the vestibular mucosa of lower lip, in children under the age of 2 years, produced by friction

Introduction
Eosinophilic ulcer of the oral mucosa (EUOM) is an uncommon self-limited oral condition mostly appearing on the tongue. Several terms have been used to describe this process, such as traumatic granuloma of the tongue,
Correspondence: S Segura, MD, Department of Dermatology, Hospital del Mar, Passeig Marı´ tim 25–29, 08003, Barcelona, Spain. Tel: +34 93 2483380, Fax: +34 93 2483328, E-mail: ssegura@ imas.imim.esc Received 25 January 2008; accepted 29 January 2008

1983). sublingual ulcer. Etiopathogenic mechanisms The pathogenic mechanisms implicated in the development of EUOM are poorly understood and only a limited number of studies have been specifically designed to elucidate the origin of this condition. although a significant numbers were detected in the normal surrounding tissue (Regezi et al. Several clinical features and epidemiological data seem to suggest that trauma may play a role in the development of this disorder: (i) A traumatic event is recorded in a variable proportion of cases of EUOM ranging from 0 to 100% of the cases (average 39%) (Bhaskar and Lilly. The absence of pain sensation leads to oral self-inflicted lesions after the appearance of incisors teeth. (ii) the lesions are frequently located on the tongue where traumatisms are frequent. sublingual growth in children. A lack of significant synthesis of transforming growth factors by eosinophils has been demonstrated in traumatic ulcerative granuloma with stromal eosinophilia. 1983). . and another among the sixth and seventh decade. This etiologic factor. Hirshberg et al. The authors proposed to include both manifestations in one entity as they shared distinct histological and clinical characteristics (Elzay. in addition to stromal eosinophilia. in the context of nursing and teething. However. El-Mofty et al. an increase in mast cells (intact and degranulating) was observed. as well as dental appliances and dentures may be more common. In all control tissues. could induce an intense inflammatory reaction giving rise to a mast cell-eosinophil reaction similar to that noted in the studies on bronchial asthma. when missing and malposed teeth. 1993. 1981). Rakocz et al (1987) first associated this condition with familial dysautonomia. A traumatic disruption of the oral mucosa would facilitate the action of a non-identified etiologic factor (microorganisms. As most traumatic oral ulcers are devoid of eosinophils. However. 1993). 1964. but other synonyms were referred in the early literature. (2006) demonstrated the presence of aggregates of TIA-1 positive cells. Elzay histologically compared 41 cases of EUOM with 30 patients with a variety of inflammatory conditions affecting the oral mucosa (control group) and biopsies from normal oral mucosa (Elzay. Their interaction with fibroblasts may result in a contribution towards wound healing via the synthesis of transforming growth factor (TGF) a and b. It was most commonly called Riga–Fede disease. in a predisposed subject. 1996). because it may be the presenting sign of an underlying neurological disorder in this population (Eichenfield et al. Bhaskar and Lilly (1964) reported the development of lesions Oral Diseases similar to EUOM after experimentally producing repeated injuries to the tongue. the exact role of mast cells in the pathogenesis of EUOM remains controversial. different attempts have failed to demonstrate viral particles and⁄or ultrastructural dense immune deposits in clear-cut cases of EUOM. Other authors have suggested that trauma is only a contributing factor in the development of EUOM and that probably some viral or toxic agents could be implicated (Tang et al. 1983). as demonstrated in a study using a mice wound-healing model (Wong et al. An increased number of mast cells in the peripheral underlying connective tissue were also detected by El-Mofty et al (1993). Regezi et al (1993) found scarce numbers of mast cells in EUOM infiltrates. A possible interaction between mast cell. eosinophils were absent whereas a light to moderate population of mast cells was observed in normal and inflamed oral tissue.Eosinophilic ulcer of oral mucosa S Segura and RM Pujol 288 Table 1 Clinical differential diagnosis for oral ulcers Infections Syphilis Herpes Tuberculosis Histoplasmosis Tumors Squamous cell carcinoma Histiocytosis X Lymphoma Salivary gland tumours Autoimmune diseases Discoid lupus erythematosus Wegener’s granulomatosis Others Major apthous ulcers Eosinophilic ulcer of the oral mucosa between the tongue or lip and teeth. A possible additional role of cytotoxic T cells causing mucosal damage in EUOM has also been suggested. toxins or foreign proteins) into the connective tissue. 2006). reporting 41 new cases with clinical and histological descriptions. 1989. and reparative lesion of the tongue (Elzay. 2006). several hypotheses have been proposed to explain the prominent eosinophilic infiltrates observed in this lesion. 1993). Hirshberg et al. one peak during the first 2 years of life. 2004). Zaenglein et al. 2002). In EUOM cases. these results were not confirmed by von Domarus et al (1980)after performing similar investigations. Doyle et al. Elzay. A possible direct pathogenic role of cytokine and chemotactic factors released by eosinophils in the development of EUOM has been hypothesized. Nevertheless. Thus. Histological features of this condition were described by Fede in 1890. a marker of cytotoxic T cells in 12 cases of TGSE (Hirshberg et al. sublingual granuloma. In 1964. Conversely. Recent studies have shown that eosinophils may also interact with fibroblasts and endothelial cells (Munitz and Levi-Schaffer. 1990. early recognition of this entity is important. 1983. a release eosinophil chemotactic factors and tissue eosinophilia has also been postulated. This phenomenon may explain the frequent delayed healing observed in these lesions (Elovic et al. and (iii) two peaks of age incidence have been identified in EUOM. 2002. In 1983. Garcia et al. such as Riga’s disease. Elzay revised 19 cases from literature of both traumatic eosinophilic granuloma and Riga-Fede disease.

beginning at 6–8 months of age. The lesion may show a peripheral erythema. In extremely rare cases. 2002. Velez et al. Pain can be associated with variable proportion of cases (from 17% to 100%) and may cause a significant impairment of food intake. Atypical clinical forms that manifested as erythematous macules. Elzay. The designation of Riga–Fede disease applies specifically to infants and children younger than 2 years with this disorder. the socalled Riga-Fede disease. 2002) or other disorders characterized by self-mutilation causing similar lesions (Lesch–Nyhan and Gaucher’s disease). The inflammatory infiltrate is composed of small round lymphocytes. El-Mofty et al. In contrast. principally the lower incisors. There is a slight female predominance in most of the series and a peak on incidence between the sixth and seventh decades of life. 1997. 1993. floor of the mouth. 289 Histopathology Microscopically. A dense diffuse submucosal polymorphous inflammatory infiltrate involving occasionally the overlying epithelium is usually noted. Some authors (Regezi et al. under an ulcerated mucosa. the lesions often arise on the ventral surface of the tongue or the lingual frenum along the midline because of contact with the adjacent mandibular incisors during breastfeeding. from few millimeters to several centimeters in diameter. with a variable proportion of cells expressing histocytic (CD68) or dermal dendrocyte (factor XIII) markers. EUOM usually manifests as a rapidly developing solitary ulcer. Rakocz et al. 1993). 1989). 1993. such as congenital autonomic dysfunction with universal pain loss. Garcia et al. 1964. and scattered submucosal S100positive cells (Regezi et al. but it also can arise (in decreasing order of frequency) on the lips. Hirshberg et al. 1993. Alobeid et al. 1997. 1983. a poorly formed granulation tissue showing an increased number of capillaries with prominent endothelial cells is usually observed. Table 2 illustrates a review of clinical features of the largest series of EUOM published in the literature (Bhaskar and Lilly. association with enlarged regional lymph nodes has been noted (El-Mofty et al. 1987. and retromolar area. No obvious previous trauma. Segura et al. Although EUOM is often a solitary ulcer. Ficarra et al. Doyle et al. In a histopathological review of 38 cases of EUOM. Any mucosal surface can be affected. multiple or metachronus lesions (new lesions on other oral sites) (Doyle et al. familial dysautonomia (Riley–Day syndrome) (Axelrod et al.Eosinophilic ulcer of oral mucosa S Segura and RM Pujol Clinical features Clinically. 1993). 1993). In rare instances. 1989. (1993) in an immunohistochemical study of a series of nine cases of EUOM. 2006). The ulcers usually regress spontaneously in less than a month. 1993). a white or yellowish base and fibrinous membrane on the surface (Figure 1). El-Mofty et al. Onset of the lesions is usually concomitant with the eruption of the primary teeth. 2004. This infiltrate tends to extend to the deeper underlying soft tissue. the tongue (lateral and dorsal surfaces) is the most common location. showing occasional nuclear atypia. 1989. Eichenfield et al. 2006) have also been reported. Zaenglein et al. Oral Diseases Figure 1 A 67-year-old man presenting with a painful ulcer on the lateral side of tongue appeared 4 weeks before consultation. The second most frequent locations are the buccal mucosa and mucobuccal fold. Garcia et al. El-Mofty et al. In contrast. (1993) noted that degeneration and loss of muscle fibers were an almost constant finding (El-Mofty et al. a pediatric variant of the EUOM. abundant polymorphonuclear eosinophils and other inflammatory cells (neutrophils. may be the presenting sign of an underlying neurologic disorder. persistent lesions lasting several months or even more than a year have been reported (Doyle et al. with elevated and indurated borders arising in the oral cavity or on the lower lip. Large mononuclear cells with round to ovoid pale nuclei. 1995). however. gingiva. El-Mofty et al. 1983. muscle fibers and salivary glands (Figure 2). Associated internal disease is uncommon in adults and patients with this condition are otherwise healthy (Mezei et al. 1993) pointed out that the population of large mononuclear cells is heterogeneous. suggesting that they may correspond to myofibroblasts (El-Mofty et al. 2002). Clinical features of the lesion showing an ulcer with slightly elevated borders and fibrinous surface. although some of the patients may develop recurrences (Doyle et al. observed that these atypical large cells were positive only for vimentin and lacked expression of all lymphoid and histiocytic markers. non-specific erythroplakic or leukoplakic lesions have also been reported. 1990. . intermingled in the inflammatory infiltrate are also frequently observed. 1989. palate. Degranulation of eosinophils is commonly noted. accounting for more than half the patients. Regezi et al. In children. plasma cells and histiocytes).

2 Tongue (19) Buccal mucosa (8) Vestibule (7) Floor of the mouth (3) Lower lip (1). upper lip (1) Not stated (2) Tongue (7) 2 weeks–6 Buccal mucosa (1) months 2 weeks–24 Tongue (10) months Buccal mucosa (1) Tongue (7) Buccal mucosa.2) Not stated 38 57 (6–88) 1:1.8) Not ulcerated (1) Synchronous lesions (2) Ulceration (27) Indurated lesion (13) Not stated 17% Not stated Size (mean) Previous trauma (%) None 5 cases (30) Course (follow up) Author (Year of No.1:1 Tongue (6) Lip (1) Tongue (10) Buccal mucosa (2) Alveolar mucosa (2) Floor of the month (1) No recurrence (1–2 years) 5 cases metachronus lesions 21 cases (51) No recurrence (3 months–6 years) Slow healing in 2 cases Not stated 7 cases (18) 2 cases with metachronus lesions Eosinophilic ulcer of oral mucosa S Segura and RM Pujol Elzay (1983) 41 58 (14–92) 1:1 Surgery (6) Radiation (1) 2 weeks– Complete 6 months excision (10) Healed after biopsy (3) Topical steroids (2) 3–120 days Complete excision (33) Healed after biopsy (8) El-Mofty et al (1993) 0. frenum (1) Gingiva (1). vestibule and floor of the mouth (5) Days to 1 year Hirshberg et al (2006) 12 49 (14–87) 1:1 Ulceration (7) Not stated 50% Nodule (1) Unique ulcer with 0. Mean Sex publication) cases age (range) (M:F) 7 37 (20–59) 2.5:1 Bhaskar and Lilly (1964) Doyle et al (1989) 15 62 (42–77) 1.4–2 cm (1.3–5 cm (1.5 Ulceration (19) Indurated lesion (16) Red lesion (3) 8 59 (10–87) 1:3 Not stated Remove traumatic factor Not stated 11 (100) Not stated 1 case metachronus lesion Regezi et al (1993) Garcia et al (2002) 11 62 (41–81) 1:1.290 Oral Diseases Table 2 Clinical features of main series of eosinophilic ulcer of the oral mucosa reported in the literature Clinical features Pain Not stated Not stated 14–63 days Localization Duration Treatment Ulceration Ulceration (14) 0. palate (1) Tongue (16) Weeks to Buccal mucosa and months fold (15) Retromolar (3) Palate (1).5–6 cm (2.2) 100% indurate borders (10) Two symmetric ulcers (1) Ulceration with Not Mild pain most rolled-up margins (11) stated of cases Exophytic mass (1) Complete excision or healed after biopsy 4 (30) No recurrence .

Pilolli et al. (b) H&E. atypical large cells were present. but clonality could not be demonstrated in any of the lesions (Segura et al. Original magnification 40·. 1997). immunohistochemical and molecular studies of 12 cases of EUOM. (b) H&E. (f) Abundant histiocytes throughout the lesion. Hirshberg et al. Original magnification 100·. slighty fewer than T-lymphocytes. 2004. Occasional reports of patients Oral Diseases . In the latter case. (d) CD3. Positive B-lymphocytes. 2006 Segura et al. Detail of the infiltrate consisting of eosinophils. 2006). Histological section of a biopsy from the patient showing a mixed inflammatory infiltrate in the deep submucosa. Hirshberg et al. a monoclonal rearrangement of the TCRc genes was detected in the oral tissue. Mixed inflammatory infiltrate extending into the submucosa and the striated muscle fibres. (a) (b) (c) Figure 3 (a) Ulcerated nodule on the upper lip in an old lady. 2007). small lymphocytes. Ficarra et al. 2006. Positive small T-lymphocytes within the infiltrate. (2006) performed histological. Original magnification 400·. (c) CD30. histiocytes and neutrophils.Eosinophilic ulcer of oral mucosa S Segura and RM Pujol 291 (a) (b) (c) (d) (e) (f) Figure 2 Histopathological sections and immunohistochemical stains of a case of EUOM. Original magnification 400·. Biopsy of the tongue ulcer shows an ulcerated surface and necrosis of the epithelium with inflammatory cells in the underlying submucosa. Original magnification 200·. (1997) described the first case of EUOM in which a proliferation of CD30 atypical large mononuclear cells was identified suggesting that EUOM could also be related to the spectrum of CD30 positive lymphoproliferative disorders (Ficarra et al. (c) H&E. with five cases of CD30+ cells that were scattered in four of them and presented with aggregates and one case forming small clusters infiltrating the underlying muscle. Aggregates of CD30-positive large atypical cells within the infiltrate. They found that in seven cases. (e) CD20. Several authors have also demonstrated the presence of scattered or even clusters of CD30 positive large atypical cells in EUOM lesions (Alobeid et al. We recently reported an old woman with two metachronic EUOM that exhibited aggregated CD30 positive large atypical cells in both biopsy specimens. Original magnification 400·. note the presence of large atypical cells and eosinophils. but not in the bone marrow biopsy or in peripheral blood specimen (Hirshberg et al. 2006) (Figure 3). (a) H&E. Original magnification 200·.

In oral tuberculosis. ulcers or even tumors have been also described (Bartralot et al. As the presence of large atypical CD30+ cells has been reported in a wide range of infectious. Histologically. 1996). Kim et al. Histologically. Special stains for mycobacteria may confirm the diagnosis. 2001. palate and tongue may also be affected. The observation of an EUOM that manifested clinically as a rapidly enlarging oral ulceration with indurated margins could lead to suspect the diagnosis of oral squamous cell carcinoma. but the inflammatory infiltrate has a predominantly perivascular distribution and is composed of lymphoid cells and many plasma cells. angiolymphoid hyperplasia with eosinophilia (ALHE) and Kimura disease. it is characterized by the presence of a polymorphous infiltrate with abundant eosinophils and proliferation of Langerhans’ cells that characteristically exhibit an atypical reniform nucleus and are S-100 and CD1a-positive. these lesions are clinically and histologically indistinguishable from EUOM and probably correspond to a superficial variant of this disorder. When mandibular or maxillary bone involvement is present. . Histologically. as pointed out by other authors (Hirshberg et al. The identification of Treponema pallidum spirochetes in mucosal biopsy specimens either by silver-impregnation staining techniques (Warthin–Starry stain) or immunohistochemically in addition to serologic tests may permit to establish the diagnosis.1993). In such instances. Lesions are usually multiple and recurrent and concomitant skin lesions may also be present.Eosinophilic ulcer of oral mucosa S Segura and RM Pujol 292 presenting skin nodules preceding the development of oral lesions and disclosing in both lesions an identical monoclonal rearrangement of the TCRc chain gene have been reported (Alobeid et al. 2003. ruling out malignancy. this diagnosis can be easily excluded after performing a biopsy that will show the bland histopathological picture of EUOM. which may be focal. plaques. at the base of the ulcer. the possibility that the observed lesions could correspond to a rare example of lymphomatoid papulosis with oral involvement could not be completely ruled out. 1985). Gallardo et al. direct immunofluorescence studies may be helpful. 2006). and a predominantly lymphocytic dermal infiltrate. When present. In primary syphilis. 2006). Mucosal involvement is a rare phenomenon in ALHE. A necrotizing bacterial Oral Diseases infection can be easily excluded by histopathological study. Cepeda et al. interstitial. 2004). In our opinion. However. such as primary syphilis (syphilitic chancre) and some granulomatous mycobacterial (oral tuberculosis). DLE may present as chronic ulcers on the oral mucosa. Langerhans’ cell histiocytosis (eosinophilic granuloma) is frequently included in the differential diagnosis of EUOM. Moreno-Ramirez et al. the infiltrate is more superficial and rarely extends to the underlying muscle. However. fungal (histoplasmosis) or even necrotizing bacterial infections. In contrast to EUOM. vacuolar degeneration of the basal layer. Histologically. 2002. EOUM may overlap with other entities such as atypical histiocytic granuloma (AHG). but the buccal mucosa. the observation of an inflammatory infiltrate with abundant eosinophils and a marked vascular proliferation with bizarrely shaped blood vessels is usually noted. Small spores surrounded by a clear space can be identified within histiocytes and giant cells with H&E stains. Histological features of mucosal DLE lesions show hyperkeratosis. Occasional large atypical cells are also noted showing ultrastructural (presence of lisosomes) (Eversole et al. 1985) and immunohistochemical (CD68+ expression) histiocytic cells (Regezi et al. Histologically. Atypical histiocytic granuloma is a controversial entity that manifests as a benign self-limited ulcer often developing on the gingiva. The clinical differential diagnosis should also include several infectious disorders. 2002. parasitic and inflammatory disorders (Hwong et al. 2003). Leinweber et al. disturbed epithelial maturation with reactive cytological atypia. it often manifests as a solitary asymptomatic nodule. although erythematous macules. sarcoidosis and discoid lupus erythematosus (DLE). being more obvious with PAS or Grocott Methenamine–Silver stain. alternating epithelial hyperplasia and atrophy. It is not clear if these represent individualized entities or variants of one common spectrum of disorders. Oral ulcers observed in disseminated histoplasmosis differ histologically from EUOM by the presence of areas of tissue necrosis in combination with a granulomatous inflammatory infiltrate with occasional multinucleated giant cells. 2002. 2003. Differential diagnosis The diagnosis of ulcerative lesions affecting the oral mucosa is usually difficult because different process may share a similar clinical appearance (Table 1). In difficult cases. Other clinical differential diagnoses are Wegener’s granulomatosis. perivascular or band-like. we can speculate that CD30positive cells observed in EUOM could correspond to an activated T-cell lymphocytic population within the context of a reactive lesion. the exact pathogenetic significance of this phenomenon remains elusive. the ulcer is usually painless and a regional enlarged lymph node is present. the observation of a necrotizing granulomatous inflammation is a constant feature. A lymphoid component is also present and may show a tendency to form lymphoid follicles or aggregates (Bartralot et al. Cesinaro and Maiorana. These cells exhibit mild to moderate pleomorphism and mitotic activity (Eversole et al. as well as available molecular studies by PCR for the detection of Mycobacterium tuberculosis and mycobacterial cultures. numerous vessels with prominent endothelial cells are also present. Oral lesions tend to develop on the upper lip. it is characterized by a polymorphous submucosal infiltrate with lymphohistiocytic cells and eosinophils. Gram stain and microbiological cultures. local pain and occasional gingival swelling and hyperplastic gingival proliferation mimicking a periodontal disease can be observed (Eckardt and Schultze.

however. 1998. Many different therapeutic approaches for EUOM have been reported in the literature. enlarged lymph nodes and periphereal eosinophilia.Eosinophilic ulcer of oral mucosa S Segura and RM Pujol 1996. Alobeid et al. Kim et al. Most of the oral lymphomas are of B cell lineage (98%). Once malignancy is excluded by biopsy or eventual complementary studies. including cases showing features resembling EUOM. Segura et al. Isolated reports of oral benign lesions mimicking lymphomas (Ôoral pseudolymphoma’) have also been published. it could also represent a low-grade T-cell lymphoproliferative disorder (Kempf et al. Oral involvement in LyP is an exceedingly rare phenomenon and usually manifests as ulcerated nodules or papules with central necrosis on the tongue or buccal commissure. molecular studies could not demonstrate a clonal rearrangement of the TCRc genes. molluscum contagiosum and herpes virus infection. the differential diagnosis should also include the group of CD30+ primary cutaneous lymphoproliferative disorders. 1970). gold acupuncture reaction. 2002) more than a reactive vascular disorder as had been previously hypothesized (Peters et al. no treatment is necessary. Recent studies have demonstrated a monoclonal T-cell population in some cases of ALHE suggesting that in some cases. curettage. phenotypic and molecular features. Pilolli et al. As in some cases of EUOM. Hirshberg et al. 2005). which can mimic LyP. they might represent a particular subset of EUOM (Alobeid et al. It is mainly observed in oriental subjects and it clinically manifests as the association of deep dermal or subcutaneous nodules or tumors. Razquin et al. Leinweber et al. and in many instances. large and often ulcerated nodule [anaplastic large T-cell lymphoma (ALCL)] and share the expression of CD30 antigen as a common phenotypic hallmark (clusters of CD30+ cells in LyP and more than 75% in ALCL) (Willemze et al. Savarrio et al. firm. The etiologic identification and avoidance of a possible persistent mucosal traumatism are mandatory (extraction or restoration of the causative teeth. EUOM should be added to the list of reactive inflammatory disorders and neoplastic diseases. Other therapeutic modalities include intralesional or oral corticosteroids (Mezei et al. In isolated and selected cases. 1996. 2005). clusters (Ficarra et al. but lacking atypical large cells. 2007) CD30+ large atypical cells have been observed. 1991). Oral lymphomas are rare. Cepeda et al. Cesinaro and Maiorana. Probably. 2002. Some authors have postulated that when these lesions are observed in oral mucosa. such as arthropod bite reaction. 2002. Most authors believe that Kimura disease has to be differentiated from ALHE (Chun and Ji. 2007). AHG or LyP. 2002. among others (Hwong et al. In cases of painful lesions. 2003. It probably corresponds to a heterogeneous entity. 293 Treatment Eosinophilic ulcer of the oral mucosa is generally a self-limiting disorder that tends to resolve spontaneously in a few weeks. Hirshberg et al. mostly reported in oral medicine and poorly referred in dermatologic literature. topical antibiotics. The definite diagnosis of LyP should always be established on the basis of the clinical. 2006). the better approach is to wait and see. despite there being no conclusive evidence of its efficacy. although a local traumatic event has been often incriminated. Pujol et al. Kimura disease is a chronic inflammatory process of unknown origin. but without fulfilling the typical diagnostic features of these disorders. This approach seems especially indicated in cases with persistent lesions. 2004. Hirshberg et al. always associated with the characteristic cutaneous lesions. development of new lesions in other mucosal sites may occur. whereas in cases exhibiting aggregates of those cells. self-healing papulo-nodular eruption [lymphomatoid papulosis (LyP)] or as a solitary. Moreno-Ramirez et al. Topical steroids in cream or mouthwashes can be also prescribed. but some examples of both ALCL and LyP involving the oral mucosa have been reported (Rosenberg et al. 1997. The lesions of both disorders are usually limited to the skin. 2003). The most frequently performed therapy is surgical excision. Gallardo et al. scabies. Conclusions Eosinophilic ulcer of the oral mucosa is a rare illdefined condition. 2006) or scattered (Alobeid et al. 1992). 1995). (del Rı´ o et al. 2006). topical or oral analgesics can be prescribed. 2002. The etiology is unknown. and a majority of them (58%) correspond to diffuse large B-cell lymphomas. accounting for 2–5% of all oral malignancies. 2006. and radiographic destruction of bone are the most frequent clinical signs in oral lymphomas (Kemp et al. 2003. 1997). 1999. 2000. 2006. Involvement of the oral mucosa that manifested as ulcerated nodules (mainly on the hard palate) has rarely been reported (Terakado et al. 2004. and criotherapy (Shapiro and Juhlin. ulceration. In most of the cases exhibiting scattered CD30-positive cells. 2001. The occasional observation in EOUM of large atypical lymphoid cells may raise the histopathological differential diagnosis with some malignant lymphoproliferative disorders. Histologically. Sciubba et al. Kato et al. recurrent. radiotherapy has also been advocated (Bhaskar and Lilly. change or repair of the prosthesis). 1964). which includes several groups of disorders. 2004. However. Ray et al. 2004). histopathological. 1986). Swelling. in LyP CD30+ cells are found in clusters and their number is usually higher than that observed in EUOM. verruca vulgaris. Eosinophilic ulcer of the oral mucosa is characterized by rapidly growing ulcers with indurate borders that Oral Diseases . displaying a marked component of germinal centers. CD30+ primary cutaneous lymphoproliferative disorders clinically manifest as a chronic. No further local recurrences are usually noted after excision. it is characterized by a prominent infiltrate of lymphoid cells and eosinophils. T-cell clonality could be found (Alobeid et al.

Pagerols X. Geary W. Experimental study on the Ôtraumatogenic’ eosinophilic granuloma of the tongue. Gallardo F. Traumatic granuloma of the tongue (Riga-Fede disease): association with familial dysautonomia. Chun SI. Verruca vulgaris with CD30-positive lymphoid infiltrate: a case report. Toll A. O’hara C (2008). Tomita Y. Ulcerated granuloma e osinophilicum diutinum of the tongue. Vives P (2002). Hjorting-Hansen E. These lesions may be better classified within the spectrum of CD30-positive disorders. Atypical histiocytic granuloma. Galli SJ. Pearson J (1983). Kim KJ. Elzay RP (1983). Traumatic ulcerative granuloma with stromal eosinophilia (Riga-Fede’s disease and traumatic eosinophilic granuloma). Ann Dermatol Venereol 129: 871–873. Am J Clin Pathol 121: 43–50. Involvement of the tongue by lymphomatoid papulosis. Curco N. These cells have been demonstrated to correspond either to histiocytic cells. Hwong H. Schultze A (2003). Angiolymphoid hyperplasia with eosinophilia affecting the oval mucosa: report of a case and a review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 105: 194–201. Willer M (1980).Eosinophilic ulcer of oral mucosa S Segura and RM Pujol 294 outline a wide clinical differential diagnosis. Milligan L. Eichenfield LF. ultrastructural. Bartralot R. Angiolymphoid hyperplasia with eosinophilia: evidence for a T-cell lymphoproliferative origin. Persistent atypical lymphocytic hyperplasia following tick bite in a child: report of a case and review of the literature. Jones D. Kemp S. Elovic AE. Barcelona. Frizzera G (2004). J Oral Maxillofac Surg 47: 349–352. ´ Garcia M. Noonan V. Kempf W. Oral and maxillofac pathol 75: 716–722. Akrish S et al (2006). showing occasionally cellular atypia. J Pediatr 116: 742–744. Pan LX. and histochemical findings in an unusual pseudomalignant reactive lesion of the oral cavity. Cash R. 81: 672–681. Although in adults it is not associated with underlying disease. Haeffner AC. Am J Dermatopathol 24: 260–263. Prieto VG et al (2001). Traumatic ulcerative granuloma with stromal eosinophilia: a reactive lesion of the oral mucosa. Traumatic eosinophilic granuloma of the oral mucosa a CD-30+ (Ki1) lymphoproliferative disorder? Oral Oncol 33: 375–379. Histology is characterized by a prominent eosinophilic infiltrate. Pediatr Dermatol 18: 481–484. Kabani S. J Pediatr 103: 60–64. Cepeda LT. Raspall G. Acta Derm Venereol 41: 235–239. Oral Surg Oral Med Oral Pathol 18: 206–218. CD30-positive T-cellrich pseudolymphoma induced by gold acupuncture. Lack of TGF-alpha and TGF-beta 1 synthesis by human eosinophils in chronic oral ulcers . Eckardt A. Choi JH et al (2002). Honig PJ. CD30 antigen expression in cutaneous inflammatory infiltrates of scabies: a dynamic immunophenotypic pattern that should be distinguished from lymphomatoid papulosis. Br J Dermatol 146: 882–884. Oral Diseases . Bhaskar SN. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: clinical and histopathologic differences. Hoppe W. Cesinaro AM. Baden E (1989). its presence in infants (the so called Riga–Fede disease) should exclude a neurological disease. Ji HG (1992). A form of Ôtraumatic eosinophilic granuloma’. Congenital autonomic dysfunction with universal pain loss. Nelson L (1990). The second histological hallmark is the presence of variable numbers of large cells. Eosinophilic ulcer of the oral mucosa. Doyle JL. Gallagher G. Dtsch Zahnarztl Z 35: 90–92. Huguet P. Wick MR. Oral Surg Oral Med Oral Pathol 55: 497–506. Lee MW. Eosinophilic ulcer. Weller PF. This condition is characteristically self-healing and has a benign course. Gallagher GT. Author contributions Manuscript concept and design: Sonia Segura. Hum Pathol 33: 1023–1029. Maxillofacial manifestations of Langerhans cell histiocytosis: a clinical and therapeutic analysis of 10 patients. Wong DT (1996). The occasional observation of large CD30+ cells seems to be related to a reactive pattern of activated T or B lymphocytes simulating a lymphoproliferative disorder as has been described in several reactive conditions. Ficarra G. CD30-positive atypical lymphoid cells in common nonneoplastic cutaneous infiltrates rich in neutrophils and eosinophils. Kidd PM (1985). Traumatic granuloma of the tongue (human and experimental). Zepter K et al (2002). Hirshberg A. Axelrod FB. El-Mofty SK. Report of 38 new cases with immunohistochemical observations. Miller AS (1993). Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Am J Clin Pathol 126: 522–529. Hisai H (1998). Yoshida K. Am J Dermatopathol 20: 522–526. Garcia-Patos V. Br J Dermatol 134: 744–748. Schmidt H (1961). Oral Oncol 39: 687–694. J Cutan Pathol 29: 368–373. Romagnoli P (1997). Am J Surg Pathol 27: 912–918. Kato N. Tarroch X. Lilly GE (1964). Eosinophil-rich CD30+ lymphoproliferative disorder of the oral mucosa. Eversole LR. Budel L. Kabani S. critical revision of the manuscript: Ramon M Pujol. Leider AS. ` ´ Ulcere eosinophilique de la muqueuse buccale : 11 cas. References Alobeid B. Amariglio N. Hueto J. drafting of the manuscript: Sonia Segura. Acknowledgement We thank the Department of Dermatology from Hospital Clinic. The significance and etiopathogenia of this phenomenon are not well understood. for lending us the clinical and histological images from Figure 3. Barranco C. myofobroblastic cells or activated lymphoid cells. Swanson PE. Oral non-Hodgkin’s lymphoma: review of the literature and World Health Organization classification with reference to 40 cases. Chapman SF. Cancer 55: 1722–1729. Prigmano F. J Am Acad Dermatol 27: 954–958. Light microscopic. von Domarus H. Castells A (1996). Maiorana A (2002). Jacobsen PL. Horenstein MG (2003). Report of a case. Eosinophilic ulcer of the oral mucosa cannot be considered currently a distinct entity and may be best regarded as a reactive pattern of unclear etiology. Pujol RM (2002). However. Pieretti M. there is a subset of cases of EUOM that exhibit aggregates of CD30+ cells in addition to a monoclonal rearrangement of TCRc gene.

Eosinophilic ulcer of the tongue report of two cases and review of the literature. Pujol RM. Int J Oral Maxillofac Surg 31: 222–224. Orlow SJ (2002). Oral pseudolymphoma: a report of two cases. Romero D. Juhlin EA (1970). herpes varicella⁄zoster): a broad spectrum of presentations with common pseudolymphomatous aspects. Garcı´ a Puente L. Eosinophilic ulcer of the oral mucosa. Clin Exp Dermatol 22: 154–156. Report of two cases and review of the literature. Sciubba J. Slootweg PJ (1996). ´ Segura S. ´ del Rı´ o E. Kojou T (2002). Oral Surg Oral Med Oral Pathol 75: 723–727. Alamillos FJ. Primary extranodal CD3O-positive T-cell non-Hodgkins lymphoma of the oral mucosa. Angiolymphoid hyperplasia with eosinophilia of the tongue: report of a case and review of the literature. Daniels TE. Ferrando J. Oechler HW. Rosenberg A. Ray V. Am J Clin Pathol 75: 420–425. Boisseau-Garsaud AM. J Cutan Pathol 30: 473–475. A case of Kimura’s disease of the hard palate. Jaffe ES. Int J Oral Maxillofac Surg 25: 57–59. Mayayo E. Sanchez Yus E. O’Rourke N. Hodach AE. Eosinophilic ulcer of the oral mucosa: another histological simulator of CD30+ lymphoproliferative disorders. Requena L. Histopathologic features of cutaneous herpes virus infections (herpes simplex. Fitzsimons EJ (1999). Cutaneous pseudolymphoma in association with molluscum contagiosum in an elderly patient. Scivetti M. Sie-Go DM. Muret MP. Allergy 59: 268–275. Biesma DH. J Cutan Pathol 24: 51–55. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90: 195–204. Oral angiolymphoid hyperplasia with eosinophilia. Garcia-Escudero A. Tang TT. Familial dysautonomia with Riga-Fede’s disease: report of case. Wong DT. Traumatic ulcerative granuloma with stromal eosinophilia of the oral mucosa: histological and immunohistochemical analysis of three cases. pontaneous regression of an anaplastic large cell lymphoma in the oral cavity: first reported case and review of the literature. Velez A. Savarrio L. Oral Oncol 35: 609–613. Rodas J. Bordes R. Lucchese A. Maiorano E. Matsumura T. Meehan SA. Oral involvement in lymphomatoid papulosis. Rev Med Interne 24: 253–256. Frand M.and electron-microscopic study. Takebayashi T. Shapiro L. Am J Pathol 143: 130–142. Moreno-Ramirez D. Oral Surg Oral Med Oral Pathol 61: 73–79. Altini M. Dean A. Rakocz M. J Am Acad Dermatol 33: 734–740. Am J Surg Pathol 30: 50–58. Critical review of lymphomatoid papulosis of the oral cavity with case report. Zaenglein AL. Alomar A (2005). Estrach T (2006). Cerroni L (2006). Eosinophils: Ônew’ roles for Ôold’ cells. Glicklich M. A light. Zarbo RJ. Dunlop DJ. Peters E. Characterization of the cellular infiltrate. Favia G (2007). Dermatology 210: 53–57. Citores A. Kimura’s disease on the hard palate in a patient from Martinique. WHO-EORTC classification for cutaneous lymphomas. Pilolli GP. Yang J et al (1993). Oral traumatic granuloma. Willemze R. Br J Dermatol 155: 460–463. Rios-Martin JJ et al (2003). Regezi JA. Greenspan JS (1993). Alvira R (1991). Brand N (1987). Hillion G (2003). Gibson J. Burg G et al (2005). Tron VA. 295 Oral Diseases .Eosinophilic ulcer of oral mucosa S Segura and RM Pujol Leinweber B. Minerva Stomatol 56: 73–79. Report of two cases. Said-Al-Naief N. Acosta A (1997). Eosinophilic ulcer of the oral mucosa: report of a recurrent case on the tongue. Fantasia J (2000). Dermatologica 140: 242–250. McCreadie SR (1981). Kerl H. Munitz A. Colomo L. Sasaki A. Kola AH (1986). Stewart WD. Hum Pathol 22: 837–839. Terakado N. Levi-Schaffer F (2004). Sequential expression of transforming growth factors alpha and beta 1 by eosinophils during cutaneous wound healing in the hamster. ASDC J Dent Child 54: 57–59. Chang MW. ´ Vazquez Veiga H (1997). Mezei MM. Razquin S. Extensive Riga-Fede disease of the lip and tongue. Axelrod FB. Donoff RB. Mascaro JM Jr. J Am Acad Dermatol 47: 445–447. Rivers JK (1995). Bergua P. Blood 105: 3768– 3785. Ulcerative eosinophilic granuloma of the tongue.