Eosinophilic Ulcer of the Oral Mucosa: a Distinct Entity Or a Non-Specific

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 histopathological 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 eosinophils in the development of EUOM has been hypothesized. 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 the context of nursing and teething, and growth factors by eosinophils has been demonstrated another among the sixth and seventh decade, when in traumatic ulcerative granuloma with stromal eosin- missing and malposed teeth, as well as dental appliances ophilia. This phenomenon may explain the frequent and dentures may be more common. In 1964, Bhaskar delayed healing observed in these lesions (Elovic et al, and Lilly (1964) reported the development of lesions 1996).

Oral Diseases Eosinophilic ulcer of oral mucosa S Segura and RM Pujol 289 et al et al Clinical features 1993; Regezi , 1993; Garcia , 2002; Hirshberg et al, 2006). Clinically, EUOM usually manifests as a rapidly devel- Atypical clinical forms that manifested as erythema- oping solitary ulcer, from few millimeters to several tous macules, non-specific erythroplakic or leukoplakic centimeters in diameter, with elevated and indurated lesions have also been reported. Associated internal borders arising in the oral cavity or on the lower lip. The disease is uncommon in adults and patients with this lesion may show a peripheral erythema, a white or condition are otherwise healthy (Mezei et al, 1995). In yellowish base and fibrinous membrane on the surface extremely rare cases, association with enlarged regional (Figure 1). Any mucosal surface can be affected; how- lymph nodes has been noted (El-Mofty et al, 1993). ever, the tongue (lateral and dorsal surfaces) is the most In contrast, a pediatric variant of the EUOM, the so- common location, accounting for more than half the called Riga-Fede disease, may be the presenting sign of patients. The second most frequent locations are the an underlying neurologic disorder, such as congenital buccal mucosa and mucobuccal fold, but it also can autonomic dysfunction with universal pain loss, familial arise (in decreasing order of frequency) on the lips, dysautonomia (Riley–Day syndrome) (Axelrod et al, gingiva, palate, floor of the mouth, and retromolar area. 1983; Rakocz et al, 1987; Eichenfield et al, 1990; Pain can be associated with variable proportion of Zaenglein et al, 2002) or other disorders characterized cases (from 17% to 100%) and may cause a significant by self-mutilation causing similar lesions (Lesch–Nyhan impairment of food intake. Although EUOM is often a and Gaucher’s disease). In children, the lesions often solitary ulcer, multiple or metachronus lesions (new arise on the ventral surface of the tongue or the lingual lesions on other oral sites) (Doyle et al, 1989; El-Mofty frenum along the midline because of contact with the et al, 1993; Ficarra et al, 1997; Velez et al, 1997; adjacent mandibular incisors during breastfeeding. Alobeid et al, 2004; Segura et al, 2006) have also been Onset of the lesions is usually concomitant with the reported. There is a slight female predominance in most eruption of the primary teeth, principally the lower of the series and a peak on incidence between the sixth incisors, beginning at 6–8 months of age. The and seventh decades of life. The ulcers usually regress designation of Riga–Fede disease applies specifically to spontaneously in less than a month, although some of infants and children younger than 2 years with this the patients may develop recurrences (Doyle et al, 1989). disorder. In rare instances, persistent lesions lasting several months or even more than a year have been reported Histopathology (Doyle et al, 1989; Garcia et al, 2002). Table 2 illus- trates a review of clinical features of the largest series of Microscopically, under an ulcerated mucosa, a poorly EUOM published in the literature (Bhaskar and Lilly, formed granulation tissue showing an increased number 1964; Elzay, 1983; Doyle et al, 1989; El-Mofty et al, of capillaries with prominent endothelial cells is usually observed. A dense diffuse submucosal polymorphous inflammatory infiltrate involving occasionally the over- lying epithelium is usually noted. This infiltrate tends to extend to the deeper underlying soft tissue, muscle fibers and salivary glands (Figure 2). In a histopathological review of 38 cases of EUOM, El-Mofty et al, (1993) noted that degeneration and loss of muscle fibers were an almost constant finding (El-Mofty et al, 1993). The inflammatory infiltrate is composed of small round lymphocytes, abundant polymorphonuclear eosinophils and other inflammatory cells (neutrophils, plasma cells and histiocytes). Degranulation of eosinophils is commonly noted. Large mononuclear cells with round to ovoid pale nuclei, showing occasional nuclear atypia, intermingled in the inflammatory infiltrate are also frequently observed. Some authors (Regezi et al, 1993) pointed out that the population of large mononuclear cells is heterogeneous, with a variable proportion of cells expressing histocytic (CD68) or dermal dendrocyte (factor XIII) markers, and scattered submucosal S100- positive cells (Regezi et al, 1993). In contrast, El-Mofty et al, (1993) in an immunohistochemical study of a series of nine cases of EUOM, observed that these atypical large cells were positive only for vimentin and Figure 1 A 67-year-old man presenting with a painful ulcer on the lateral side of tongue appeared 4 weeks before consultation. No lacked expression of all lymphoid and histiocytic mark- obvious previous trauma. Clinical features of the lesion showing an ers, suggesting that they may correspond to myofibro- ulcer with slightly elevated borders and fibrinous surface. blasts (El-Mofty et al, 1993).

Oral Diseases 290 rlDiseases Oral

Table 2 Clinical features of main series of eosinophilic ulcer of the oral mucosa reported in the literature

Author (Year of No. Mean Sex Clinical Size Previous trauma Course publication) cases age (range) (M:F) features (mean) Pain Localization Duration Treatment (%) (follow up)

Bhaskar and 7 37 (20–59) 2.5:1 Ulceration Not stated Not stated Tongue (6) 14–63 days Surgery (6) None No recurrence

Lilly (1964) Lip (1) Radiation (1) (1–2 years) mucosa oral of ulcer Eosinophilic Doyle et al 15 62 (42–77) 1.1:1 Ulceration (14) 0.3–5 cm (1.8) Not stated Tongue (10) 2 weeks– Complete 5 cases (30) 5 cases (1989) Not ulcerated (1) Buccal mucosa (2) 6 months excision (10) metachronus

Synchronous lesions (2) Alveolar mucosa (2) Healed after lesions Pujol RM and Segura S Floor of the month (1) biopsy (3) Topical steroids (2) Elzay 41 58 (14–92) 1:1 Ulceration (27) Not stated 17% Tongue (19) 3–120 days Complete 21 cases (51) No recurrence (1983) Indurated lesion (13) Buccal mucosa (8) excision (33) (3 months–6 Vestibule (7) Healed after years) Floor of the mouth (3) biopsy (8) Slow healing Lower lip (1), frenum (1) in 2 cases Gingiva (1), palate (1) El-Mofty et al 38 57 (6–88) 1:1.5 Ulceration (19) 0.5–6 cm (2.2) Not stated Tongue (16) Weeks to Not stated 7 cases (18) 2 cases with (1993) Indurated lesion (16) Buccal mucosa and months metachronus Red lesion (3) fold (15) lesions Retromolar (3) Palate (1), upper lip (1) Not stated (2) Regezi et al 8 59 (10–87) 1:3 Ulceration (7) Not stated 50% Tongue (7) 2 weeks–6 Not stated Not stated Not stated (1993) Nodule (1) Buccal mucosa (1) months Garcia et al 11 62 (41–81) 1:1.2 Unique ulcer with 0.4–2 cm (1.2) 100% Tongue (10) 2 weeks–24 Remove 11 (100) 1 case (2002) indurate borders (10) Buccal mucosa (1) months traumatic metachronus Two symmetric factor lesion ulcers (1) Hirshberg et al 12 49 (14–87) 1:1 Ulceration with Not Mild pain most Tongue (7) Days to Complete 4 (30) No recurrence (2006) rolled-up margins (11) stated of cases Buccal mucosa, 1 year excision or Exophytic mass (1) vestibule and healed after ﬂoor of the mouth (5) biopsy 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. (a) H&E. Original magnification 40·. Biopsy of the tongue ulcer shows an ulcerated surface and necrosis of the epithelium with inflammatory cells in the underlying submucosa; (b) H&E. Original magnification 100·. Mixed inflammatory infiltrate extending into the submucosa and the striated muscle fibres; (c) H&E. Original magnification 400·. Detail of the infiltrate consisting of eosinophils, small lymphocytes, histiocytes and neutrophils. (d) CD3. Original magnification 400·. Positive small T-lymphocytes within the infiltrate; (e) CD20. Original magnification 400·. Positive B-lymphocytes, slighty fewer than T-lymphocytes. (f) Abundant histiocytes throughout the lesion.

(a) (b) (c)

Figure 3 (a) Ulcerated nodule on the upper lip in an old lady; (b) H&E. Original magnification 200·. Histological section of a biopsy from the patient showing a mixed inflammatory infiltrate in the deep submucosa, note the presence of large atypical cells and eosinophils; (c) CD30. Original magnification 200·. Aggregates of CD30-positive large atypical cells within the infiltrate.

Ficarra et al, (1997) described the first case of EUOM could not be demonstrated in any of the lesions (Segura in which a proliferation of CD30 atypical large mono- et al, 2006) (Figure 3). Hirshberg et al, (2006) per- nuclear cells was identified suggesting that EUOM could formed histological, immunohistochemical and molecu- also be related to the spectrum of CD30 positive lar studies of 12 cases of EUOM. They found that in lymphoproliferative disorders (Ficarra et al, 1997). Sev- seven cases, atypical large cells were present, with five eral authors have also demonstrated the presence of cases of CD30+ cells that were scattered in four of them scattered or even clusters of CD30 positive large atypical and presented with aggregates and one case forming cells in EUOM lesions (Alobeid et al, 2004; Hirshberg small clusters infiltrating the underlying muscle. In the et al, 2006 Segura et al, 2006; Pilolli et al, 2007). We latter case, a monoclonal rearrangement of the TCRc recently reported an old woman with two metachronic genes was detected in the oral tissue, but not in the EUOM that exhibited aggregated CD30 positive large bone marrow biopsy or in peripheral blood specimen atypical cells in both biopsy specimens, but clonality (Hirshberg et al, 2006). Occasional reports of patients

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

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

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

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

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