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Traumatic Ulcerative Granuloma With Stromal Eosinophilia: A Malignant-Appearing Benign Lesion
Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is an uncommon, benign, self-limited condition that is restricted to the oral mucosa, most commonly seen in the fifth to seventh decades of life.1-3 The pathogenesis of TUGSE is unknown, but current theory suggests trauma is the instigating factor. The presence of CD30+ mononuclear cells within TUGSE raises the possibility of a CD30+ lymphoproliferative disorder in some cases.4 However, because CD30+ cells are not uncommon in other benign reactive processes, they may simply represent a reactive phenomenon.3
Traumatic ulcerative granuloma with stromal eosinophilia traverses multiple disciplines, including dermatology, oral surgery, dentistry, and pathology, resulting in a diverse nomenclature including traumatic granuloma of the tongue, traumatic eosinophilic granuloma of the oral mucosa, ulcerated granuloma eosinophilicum diutinum, and eosinophilic ulcer of the oral mucosa.1,4-6 It is important to differentiate eosinophilic granuloma of the oral mucosa from the eosinophilic granuloma that is associated with Langerhans cell histiocytosis. Although both may present with oral ulceration, Langerhans cell–associated eosinophilic granuloma typically develops from underlying bone, whereas eosinophilic granuloma of the oral mucosa (TUGSE) is described as nonosseous.7,8 Furthermore, the gingiva is the most common oral site in Langerhans cell–associated eosinophilic granuloma, whereas the tongue is most commonly involved in TUGSE.8 Shapiro and Juhlin9 clearly distinguished TUGSE from Langerhans cell–associated eosinophilic granuloma in 1970. Histologically, the 2 conditions are completely different.
When ulcerative granulomas develop in the pediatric population, usually in children younger than 2 years, it is termed Riga-Fede disease.10 These children were typically breastfeeding, suckling, or teething, suggesting trauma as a triggering event. In 1961, Hjorting-Hansen and Schmidt5 described 3 separate lesions similar to Riga-Fede disease in an adult patient. Subsequently, Riga-Fede disease was grouped under TUGSE.3
Histologically, TUGSE shows an ulcerated epithelium with a polymorphic inflammatory cell infiltrate that has a large predominance of eosinophils. The infiltrate affects the superficial and deep layers of the muscle tissue and penetrates into the salivary glands. Large atypical mononuclear cells with an ovoid and pale-appearing nucleus often are present. These cells may be mitotically active and stain positively for CD30.1,4,11 CD68+ macrophages, T lymphocytes, and factor XIIIa–positive dendritic cells commonly are present.12
Given the presence of large atypical CD30+ cells in many lesions, the possibility of a CD30+ lymphoproliferative disorder has been postulated by some authors. Indeed, lymphomatoid papulosis (LyP) has been documented to involve the oral mucosa.2,4
Case Report
An 81-year-old man presented with a rapidly enlarging, 1.7×1.3-cm, vascular-appearing nodule with a collarette of mucosal epithelium on the left side of the dorsal surface of the tongue of 2 weeks’ duration (Figure 1). He denied any history of trauma, tobacco chewing, weight change, fever, or fatigue; however, he did report a 30 pack-year smoking history. There was no other pertinent medical history to include medications or allergies.
The differential diagnosis included pyogenic granuloma, granular cell tumor, squamous cell carcinoma, other neoplasms (eg, oral lymphoma, salivary gland tumors), and a traumatic blood blister from tongue biting. The patient was referred to the oral maxillofacial surgery department for an excisional biopsy, which showed a solitary ulcerated nodule with associated granulation tissue, thrombus, and fibrinoid debris (Figure 2). A surrounding dense mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was noted extending through the submucosal tissue and underlying striated muscle fibers (Figure 3). The adjacent mucosal epithelium appeared normal. CD30 staining showed only rare positive cells. These findings were consistent with TUGSE.
Due to the benign nature of TUGSE, the patient was released with symptomatic care and instructed to return for any new growth. The growth spontaneously resolved over 1 month and no recurrence or new lesions were reported 1 year later.
Comment
Despite encompassing multiple disciplines of medicine, TUGSE has minimal exposure in the dermatologic literature. It is an important clinical and histologic diagnosis that will provide reassurance to the patient when accurately identified and reduce potentially harmful treatments.
Clinical Presentation
Typically, TUGSE presents as a painful solitary nodule with a central ulcer and yellow fibrinous base. The margins of the ulcer typically have an indurated and rolled appearance.1,4 More than 50% of the lesions develop on the tongue, specifically the dorsal or lateral surfaces, but they may present anywhere in the oral mucosa.7 Traumatic ulcerative granuloma with stromal eosinophilia is a fast-growing lesion, typically developing in days to weeks. Although it spontaneously regresses, the lesion may take weeks or months to resolve. In one case, it resolved 1 year later.1 Traumatic ulcerative granuloma with stromal eosinophilia has a bimodal age distribution, generally appearing in the first 2 years of life and later in the fifth through seventh decades. The male-to-female predominance is equal.1,7,11 Reoccurrence is rare, but some reports have shown patients with multiple episodes of TUGSE.13,14
Differential Diagnosis
The clinical differential diagnosis for TUGSE includes squamous cell carcinoma, pyogenic granuloma, lymphoproliferative disorder, traumatic neuroma, Langerhans cell histiocytosis, granulomatous disorders, and oral lymphoma. Inflammatory disorders such as syphilis, Behçet’s disease, herpes, histoplasmosis, Wegener granulomatosis, and others also should be considered.
Immunohistochemistry
Immunohistochemical analysis of TUGSE lesions recently has revealed the presence of CD30+ cells. These cells are associated with cutaneous lymphoproliferative disorders including LyP, anaplastic large cell lymphoma (ALCL), and borderline CD30+ lesions, among others. Systemic diseases with CD30+ cells include mycosis fungoides, other T-cell lymphomas, and Hodgkin lymphoma.15,16 Once CD30+ cells were recognized, multiple authors began speculating there was a correlation between TUGSE and the CD30+ lymphoproliferative disorders.1,2,13 Anaplastic large cell lymphoma and LyP of the oral mucosa have been reported in several cases.17-20 One report described 2 cases of ulcerated CD30+ T-cell non-Hodgkin lymphoma of the oral mucosa, one of which showed eosinophilic infiltrates and was initially thought to be TUGSE. Based on these overlapping clinical and histologic features, the authors hypothesized there was a correlation between oral ALCL, LyP, and TUGSE.17 In one report, a patient developed multiple TUGSE lesions throughout his life, suggesting a pathologic process similar to LyP. The lesion biopsied showed that 70% of the T cells expressed CD30 (Ki-1) antigen.13
Underlying Causes
In support of an underlying immunologic process that augments the growth of these lesions, 2 separate case reports of TUGSE in the presence of human T-lymphotropic virus 1 (HTLV-1) and Epstein-Barr virus have been documented.2,21 Concurrent presentation of TUGSE and HTLV-1 in one report demonstrated eosinophilia in both the oral lesion and peripheral blood, suggesting an immunologic relationship. Furthermore, the authors postulated that local trauma initiated the development of TUGSE, providing the catalyst for the HTLV-1 carrier to develop peripheral eosinophilia.21
In the second case, a 12-year-old boy developed TUGSE in the presence of Epstein-Barr virus.2 Immunologically, this virus can be reactivated from its latent stage during immunosuppression. Epstein-Barr virus has been implicated in lymphoproliferative diseases of both B- and T-cell origin, including CD30+ ALCL and LyP.22,23 The authors in this report again hypothesized there was a correlation between lymphoproliferative disorders and TUGSE lesions.2,24
Alternatively, TUGSE may simply be a reactive process to trauma or another underlying trigger. It has been speculated that the presence of eosinophils correlates with antigen insertion into the oral mucosa, whereas other ulcers of the oral mucosa are devoid of eosinophils.1 These antigens may include microorganisms, endogenous degradation products, or foreign proteins.7,25 Additionally, the presence of CD30+ lymphocytes is not isolated to lymphoproliferative disorders. CD30+ cells have been documented in arthropod bite reactions, atopic dermatitis, drug reactions, molluscum contagiosum, and scabies, among others.1,26
Healing and Management
The length of healing in TUGSE ulcers has substantial variability, from days to up to 1 year in an isolated case.1,24 Sequential expression of transforming growth factor (TGF) α and TGF-β expressed by tissue eosinophils may be underlying factors associated with a quicker healing response as demonstrated by similar ulcers in hamsters.27 Chronic nonhealing oral ulcers, particularly TUGSE lesions that demonstrated the typical increase in eosinophils in 11 of 12 cases, showed minimal TGF-α or TGF-β expression by eosinophils, perhaps indicating a possible mechanism leading to delayed wound healing in some cases. Interestingly, incisional biopsies often led to rapid wound healing, suggesting that the biopsy itself allowed for a transition back to the regular wound-healing processes.28
Traumatic ulcerative granuloma with stromal eosinophilia spontaneously resolves on its own in most cases; however, because of the concern for malignancy, it has the potential to be overtreated.26 Symptomatic treatment only is the mainstay of therapy. The patient should be instructed to avoid trauma, and referral to a dental professional is indicated when associated with dentures or other periprosthetic devices. Diet should consist of soft foods while avoiding spicy foods. Topical or oral analgesics may be necessary if substantial pain is associated with the lesion.2 Oral prednisolone was used in a patient with concurrent HTLV-1 and TUGSE to treat peripheral eosinophilia.21 The patient’s peripheral eosinophils dropped to 1% in 1 day, and the patient’s oral lesion began to improve at day 3 and disappeared by day 10. Although TUGSE may spontaneously resolve within a 10-day period without steroids, it may be a reasonable treatment to improve healing time in an otherwise healthy individual.21,26 If there is concern for malignancy, the patient should have the lesion biopsied to provide reassurance and for the added benefit of a transition to normal healing response and decreased healing time.28
Clinical Recognition
The clinician should be aware of the possibility of a CD30+ lymphoproliferative disorder, which has been associated with TUGSE in some cases, or may simulate TUGSE both clinically and histologically. Further studies are needed to clarify the relationship between these 2 entities. Whether it is a true relationship, simple coincidence, or simply overlapping clinical and histologic features remains to be determined.
- Hirshberg A, Amariglio N, Akrish S, et al. Traumatic ulcerative granuloma with stromal eosinophilia: reactive lesion of the oral mucosa. Am J Clin Pathol. 2006;126:522-529.
- Abdel-Naser MB, Tsatsou F, Hippe S, et al. Oral eosinophilic ulcer, an Epstein-Barr virus-associated CD30+ lymphoproliferation? [published online April 5, 2011]. Dermatology. 2011;222:113-118.
- Fonseca FP, Benevenuto de Andrade BA, Coletta RD, et al. Clinicopathological and immunohistochemical analysis of 19 cases of oral eosinophilic ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115:532-540.
- Alobeid B, Pan LX, Milligan L, et al. Eosinophil-rich CD30+ lymphoproliferative disorder of the oral mucosa. Am J Clin Pathol. 2004;121:43-50.
- Hjorting-Hansen E, Schmidt H. Ulcerated granuloma eosinophilicum diutinum of the tongue. report of a case. Acta Derm Venereol. 1961;41:235-239.
- Velez A, Alamillos FJ, Dean A, et al. Eosinophilic ulcer of the oral mucosa: report of a recurrent case on the tongue. Clin Exp Dermatol. 1997;22:154-156.
- Elzay RP. Traumatic ulcerative granuloma with stromal eosinophilia (Riga-Fede’s disease and traumatic eosinophilic granuloma). Oral Surg Oral Med Oral Pathol. 1983;55:497-506.
- Val-Bernal JF, Gonzalez-Vela MC, Sanchez-Santolino S, et al. Localized eosinophilic (Langerhans’ cell) granuloma of the lower lip. a lesion that may cause diagnostic error. J Cutan Pathol. 2009;36:1109-1113.
- Shapiro L, Juhlin EA. Eosinophilic ulcer of the tongue report of two cases and review of the literature. Dermatologica. 1970;140:242-250.
- Amberg S. Sublingual growth in infants. Am J Med Sci. 1902;126:257-269.
- EI-Mofty SK, Swanson PE, Wick MR, et al. Eosinophilic ulcer of the oral mucosa: report of 38 new cases with immunohistochemical observations. Oral Surg Oral Med Oral Pathol. 1993;75:716-722.
- Regezi JA, Zarbo RJ, Daniels TE, et al. Oral traumatic granuloma: characterization of the cellular infiltrate. Oral Surg Oral Med Oral Pathol. 1993;75:723-727.
- Ficarra G, Prignano F, Romagnoli P. Traumatic eosinophilic granuloma of the oral mucosa: a CD30+ (Ki-1) lymphoproliferative disorder? Oral Oncol. 1997;33:375-379.
- Doyle JL, Geary W, Baden E. Eosinophilic ulcer. J Oral Maxillofac Surg. 1989;47:349-352.
- Liu HL, Hoppe RT, Kohler S, et al. CD30+ cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol. 2003;49:1049-1058.
- Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985;66:848-858.
- Rosenberg A, Biesma DH, Sie-Go DMDS, et al. Primary extranodal CD30-positive T-cell non-Hodgkin’s lymphoma of the oral mucosa. report of two cases. Int J Oral Maxillofac Surg. 1996;25:57-59.
- Kato N, Tomita Y, Yoshida K, et al. Involvement of the tongue by lymphomatoid papulosis. Am J Dermatopathol. 1998;20:522-526.
- Savarrio L, Gibson J, Dunlop DJ, et al. Spontaneous regression of an anaplastic large cell lymphoma in the oral cavity: first reported case and review of the literature. Oral Oncol. 1999;35:609-613.
- Sciubba J, Said-Al-Naief N, Fantasia J. Critical review of lymphomatoid papulosis of the oral cavity with case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:195-204.
- Yamazaki H, Shirasugi Y, Kajiwara H, et al. Concurrent onset of eosinophilic ulcer of the oral mucosa with peripheral eosinophilia in a human T-cell leukemia virus type I carrier. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:E43-E48.
- Dojcinov SD, Venkataram G, Raffeld M, et al. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010;34:405-417.
- Kim YC, Yang WI, Lee MG, et al. Epstein-Barr virus in CD30 anaplastic large cell lymphoma involving the skin and lymphomatoid papulosis in South Korea. Int J Dermatol. 2006;45:1312-1316.
- Pietersma F, Piriou E, van Baarle D. Immune surveillance of EBV-infected B cells and the development of non-Hodgkin lymphomas in immunocompromised patients. Leuk Lymphoma. 2008;49:1028-1041.
- Salisbury CL, Budnick SD, Li S. T cell receptor gene rearrangement and CD 30 immunoreactivity in traumatic ulcerative granuloma with stromal eosinophilia of oral cavity. Am J Clin Pathol. 2009;132:722-727.
- Marszalek A, Neska-Dlugosz I. Traumatic ulcerative granuloma with stromal eosinophilia. a case report and short literature review. Pol J Pathol. 2011;3:172-175.
- Wong DT, Donoff RB, Yang J, et al. Sequential expression of transforming growth factors alpha and beta 1 by eosinophils during cutaneous wound healing in the hamster. Am J Pathol. 1993;143:130-142.
- Elovic AE, Gallagher GT, Kabani S, et al. Lack of TGF-alpha and TGF-beta synthesis by human eosinophils in chronic oral ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:672-681.
Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is an uncommon, benign, self-limited condition that is restricted to the oral mucosa, most commonly seen in the fifth to seventh decades of life.1-3 The pathogenesis of TUGSE is unknown, but current theory suggests trauma is the instigating factor. The presence of CD30+ mononuclear cells within TUGSE raises the possibility of a CD30+ lymphoproliferative disorder in some cases.4 However, because CD30+ cells are not uncommon in other benign reactive processes, they may simply represent a reactive phenomenon.3
Traumatic ulcerative granuloma with stromal eosinophilia traverses multiple disciplines, including dermatology, oral surgery, dentistry, and pathology, resulting in a diverse nomenclature including traumatic granuloma of the tongue, traumatic eosinophilic granuloma of the oral mucosa, ulcerated granuloma eosinophilicum diutinum, and eosinophilic ulcer of the oral mucosa.1,4-6 It is important to differentiate eosinophilic granuloma of the oral mucosa from the eosinophilic granuloma that is associated with Langerhans cell histiocytosis. Although both may present with oral ulceration, Langerhans cell–associated eosinophilic granuloma typically develops from underlying bone, whereas eosinophilic granuloma of the oral mucosa (TUGSE) is described as nonosseous.7,8 Furthermore, the gingiva is the most common oral site in Langerhans cell–associated eosinophilic granuloma, whereas the tongue is most commonly involved in TUGSE.8 Shapiro and Juhlin9 clearly distinguished TUGSE from Langerhans cell–associated eosinophilic granuloma in 1970. Histologically, the 2 conditions are completely different.
When ulcerative granulomas develop in the pediatric population, usually in children younger than 2 years, it is termed Riga-Fede disease.10 These children were typically breastfeeding, suckling, or teething, suggesting trauma as a triggering event. In 1961, Hjorting-Hansen and Schmidt5 described 3 separate lesions similar to Riga-Fede disease in an adult patient. Subsequently, Riga-Fede disease was grouped under TUGSE.3
Histologically, TUGSE shows an ulcerated epithelium with a polymorphic inflammatory cell infiltrate that has a large predominance of eosinophils. The infiltrate affects the superficial and deep layers of the muscle tissue and penetrates into the salivary glands. Large atypical mononuclear cells with an ovoid and pale-appearing nucleus often are present. These cells may be mitotically active and stain positively for CD30.1,4,11 CD68+ macrophages, T lymphocytes, and factor XIIIa–positive dendritic cells commonly are present.12
Given the presence of large atypical CD30+ cells in many lesions, the possibility of a CD30+ lymphoproliferative disorder has been postulated by some authors. Indeed, lymphomatoid papulosis (LyP) has been documented to involve the oral mucosa.2,4
Case Report
An 81-year-old man presented with a rapidly enlarging, 1.7×1.3-cm, vascular-appearing nodule with a collarette of mucosal epithelium on the left side of the dorsal surface of the tongue of 2 weeks’ duration (Figure 1). He denied any history of trauma, tobacco chewing, weight change, fever, or fatigue; however, he did report a 30 pack-year smoking history. There was no other pertinent medical history to include medications or allergies.
The differential diagnosis included pyogenic granuloma, granular cell tumor, squamous cell carcinoma, other neoplasms (eg, oral lymphoma, salivary gland tumors), and a traumatic blood blister from tongue biting. The patient was referred to the oral maxillofacial surgery department for an excisional biopsy, which showed a solitary ulcerated nodule with associated granulation tissue, thrombus, and fibrinoid debris (Figure 2). A surrounding dense mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was noted extending through the submucosal tissue and underlying striated muscle fibers (Figure 3). The adjacent mucosal epithelium appeared normal. CD30 staining showed only rare positive cells. These findings were consistent with TUGSE.
Due to the benign nature of TUGSE, the patient was released with symptomatic care and instructed to return for any new growth. The growth spontaneously resolved over 1 month and no recurrence or new lesions were reported 1 year later.
Comment
Despite encompassing multiple disciplines of medicine, TUGSE has minimal exposure in the dermatologic literature. It is an important clinical and histologic diagnosis that will provide reassurance to the patient when accurately identified and reduce potentially harmful treatments.
Clinical Presentation
Typically, TUGSE presents as a painful solitary nodule with a central ulcer and yellow fibrinous base. The margins of the ulcer typically have an indurated and rolled appearance.1,4 More than 50% of the lesions develop on the tongue, specifically the dorsal or lateral surfaces, but they may present anywhere in the oral mucosa.7 Traumatic ulcerative granuloma with stromal eosinophilia is a fast-growing lesion, typically developing in days to weeks. Although it spontaneously regresses, the lesion may take weeks or months to resolve. In one case, it resolved 1 year later.1 Traumatic ulcerative granuloma with stromal eosinophilia has a bimodal age distribution, generally appearing in the first 2 years of life and later in the fifth through seventh decades. The male-to-female predominance is equal.1,7,11 Reoccurrence is rare, but some reports have shown patients with multiple episodes of TUGSE.13,14
Differential Diagnosis
The clinical differential diagnosis for TUGSE includes squamous cell carcinoma, pyogenic granuloma, lymphoproliferative disorder, traumatic neuroma, Langerhans cell histiocytosis, granulomatous disorders, and oral lymphoma. Inflammatory disorders such as syphilis, Behçet’s disease, herpes, histoplasmosis, Wegener granulomatosis, and others also should be considered.
Immunohistochemistry
Immunohistochemical analysis of TUGSE lesions recently has revealed the presence of CD30+ cells. These cells are associated with cutaneous lymphoproliferative disorders including LyP, anaplastic large cell lymphoma (ALCL), and borderline CD30+ lesions, among others. Systemic diseases with CD30+ cells include mycosis fungoides, other T-cell lymphomas, and Hodgkin lymphoma.15,16 Once CD30+ cells were recognized, multiple authors began speculating there was a correlation between TUGSE and the CD30+ lymphoproliferative disorders.1,2,13 Anaplastic large cell lymphoma and LyP of the oral mucosa have been reported in several cases.17-20 One report described 2 cases of ulcerated CD30+ T-cell non-Hodgkin lymphoma of the oral mucosa, one of which showed eosinophilic infiltrates and was initially thought to be TUGSE. Based on these overlapping clinical and histologic features, the authors hypothesized there was a correlation between oral ALCL, LyP, and TUGSE.17 In one report, a patient developed multiple TUGSE lesions throughout his life, suggesting a pathologic process similar to LyP. The lesion biopsied showed that 70% of the T cells expressed CD30 (Ki-1) antigen.13
Underlying Causes
In support of an underlying immunologic process that augments the growth of these lesions, 2 separate case reports of TUGSE in the presence of human T-lymphotropic virus 1 (HTLV-1) and Epstein-Barr virus have been documented.2,21 Concurrent presentation of TUGSE and HTLV-1 in one report demonstrated eosinophilia in both the oral lesion and peripheral blood, suggesting an immunologic relationship. Furthermore, the authors postulated that local trauma initiated the development of TUGSE, providing the catalyst for the HTLV-1 carrier to develop peripheral eosinophilia.21
In the second case, a 12-year-old boy developed TUGSE in the presence of Epstein-Barr virus.2 Immunologically, this virus can be reactivated from its latent stage during immunosuppression. Epstein-Barr virus has been implicated in lymphoproliferative diseases of both B- and T-cell origin, including CD30+ ALCL and LyP.22,23 The authors in this report again hypothesized there was a correlation between lymphoproliferative disorders and TUGSE lesions.2,24
Alternatively, TUGSE may simply be a reactive process to trauma or another underlying trigger. It has been speculated that the presence of eosinophils correlates with antigen insertion into the oral mucosa, whereas other ulcers of the oral mucosa are devoid of eosinophils.1 These antigens may include microorganisms, endogenous degradation products, or foreign proteins.7,25 Additionally, the presence of CD30+ lymphocytes is not isolated to lymphoproliferative disorders. CD30+ cells have been documented in arthropod bite reactions, atopic dermatitis, drug reactions, molluscum contagiosum, and scabies, among others.1,26
Healing and Management
The length of healing in TUGSE ulcers has substantial variability, from days to up to 1 year in an isolated case.1,24 Sequential expression of transforming growth factor (TGF) α and TGF-β expressed by tissue eosinophils may be underlying factors associated with a quicker healing response as demonstrated by similar ulcers in hamsters.27 Chronic nonhealing oral ulcers, particularly TUGSE lesions that demonstrated the typical increase in eosinophils in 11 of 12 cases, showed minimal TGF-α or TGF-β expression by eosinophils, perhaps indicating a possible mechanism leading to delayed wound healing in some cases. Interestingly, incisional biopsies often led to rapid wound healing, suggesting that the biopsy itself allowed for a transition back to the regular wound-healing processes.28
Traumatic ulcerative granuloma with stromal eosinophilia spontaneously resolves on its own in most cases; however, because of the concern for malignancy, it has the potential to be overtreated.26 Symptomatic treatment only is the mainstay of therapy. The patient should be instructed to avoid trauma, and referral to a dental professional is indicated when associated with dentures or other periprosthetic devices. Diet should consist of soft foods while avoiding spicy foods. Topical or oral analgesics may be necessary if substantial pain is associated with the lesion.2 Oral prednisolone was used in a patient with concurrent HTLV-1 and TUGSE to treat peripheral eosinophilia.21 The patient’s peripheral eosinophils dropped to 1% in 1 day, and the patient’s oral lesion began to improve at day 3 and disappeared by day 10. Although TUGSE may spontaneously resolve within a 10-day period without steroids, it may be a reasonable treatment to improve healing time in an otherwise healthy individual.21,26 If there is concern for malignancy, the patient should have the lesion biopsied to provide reassurance and for the added benefit of a transition to normal healing response and decreased healing time.28
Clinical Recognition
The clinician should be aware of the possibility of a CD30+ lymphoproliferative disorder, which has been associated with TUGSE in some cases, or may simulate TUGSE both clinically and histologically. Further studies are needed to clarify the relationship between these 2 entities. Whether it is a true relationship, simple coincidence, or simply overlapping clinical and histologic features remains to be determined.
Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is an uncommon, benign, self-limited condition that is restricted to the oral mucosa, most commonly seen in the fifth to seventh decades of life.1-3 The pathogenesis of TUGSE is unknown, but current theory suggests trauma is the instigating factor. The presence of CD30+ mononuclear cells within TUGSE raises the possibility of a CD30+ lymphoproliferative disorder in some cases.4 However, because CD30+ cells are not uncommon in other benign reactive processes, they may simply represent a reactive phenomenon.3
Traumatic ulcerative granuloma with stromal eosinophilia traverses multiple disciplines, including dermatology, oral surgery, dentistry, and pathology, resulting in a diverse nomenclature including traumatic granuloma of the tongue, traumatic eosinophilic granuloma of the oral mucosa, ulcerated granuloma eosinophilicum diutinum, and eosinophilic ulcer of the oral mucosa.1,4-6 It is important to differentiate eosinophilic granuloma of the oral mucosa from the eosinophilic granuloma that is associated with Langerhans cell histiocytosis. Although both may present with oral ulceration, Langerhans cell–associated eosinophilic granuloma typically develops from underlying bone, whereas eosinophilic granuloma of the oral mucosa (TUGSE) is described as nonosseous.7,8 Furthermore, the gingiva is the most common oral site in Langerhans cell–associated eosinophilic granuloma, whereas the tongue is most commonly involved in TUGSE.8 Shapiro and Juhlin9 clearly distinguished TUGSE from Langerhans cell–associated eosinophilic granuloma in 1970. Histologically, the 2 conditions are completely different.
When ulcerative granulomas develop in the pediatric population, usually in children younger than 2 years, it is termed Riga-Fede disease.10 These children were typically breastfeeding, suckling, or teething, suggesting trauma as a triggering event. In 1961, Hjorting-Hansen and Schmidt5 described 3 separate lesions similar to Riga-Fede disease in an adult patient. Subsequently, Riga-Fede disease was grouped under TUGSE.3
Histologically, TUGSE shows an ulcerated epithelium with a polymorphic inflammatory cell infiltrate that has a large predominance of eosinophils. The infiltrate affects the superficial and deep layers of the muscle tissue and penetrates into the salivary glands. Large atypical mononuclear cells with an ovoid and pale-appearing nucleus often are present. These cells may be mitotically active and stain positively for CD30.1,4,11 CD68+ macrophages, T lymphocytes, and factor XIIIa–positive dendritic cells commonly are present.12
Given the presence of large atypical CD30+ cells in many lesions, the possibility of a CD30+ lymphoproliferative disorder has been postulated by some authors. Indeed, lymphomatoid papulosis (LyP) has been documented to involve the oral mucosa.2,4
Case Report
An 81-year-old man presented with a rapidly enlarging, 1.7×1.3-cm, vascular-appearing nodule with a collarette of mucosal epithelium on the left side of the dorsal surface of the tongue of 2 weeks’ duration (Figure 1). He denied any history of trauma, tobacco chewing, weight change, fever, or fatigue; however, he did report a 30 pack-year smoking history. There was no other pertinent medical history to include medications or allergies.
The differential diagnosis included pyogenic granuloma, granular cell tumor, squamous cell carcinoma, other neoplasms (eg, oral lymphoma, salivary gland tumors), and a traumatic blood blister from tongue biting. The patient was referred to the oral maxillofacial surgery department for an excisional biopsy, which showed a solitary ulcerated nodule with associated granulation tissue, thrombus, and fibrinoid debris (Figure 2). A surrounding dense mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was noted extending through the submucosal tissue and underlying striated muscle fibers (Figure 3). The adjacent mucosal epithelium appeared normal. CD30 staining showed only rare positive cells. These findings were consistent with TUGSE.
Due to the benign nature of TUGSE, the patient was released with symptomatic care and instructed to return for any new growth. The growth spontaneously resolved over 1 month and no recurrence or new lesions were reported 1 year later.
Comment
Despite encompassing multiple disciplines of medicine, TUGSE has minimal exposure in the dermatologic literature. It is an important clinical and histologic diagnosis that will provide reassurance to the patient when accurately identified and reduce potentially harmful treatments.
Clinical Presentation
Typically, TUGSE presents as a painful solitary nodule with a central ulcer and yellow fibrinous base. The margins of the ulcer typically have an indurated and rolled appearance.1,4 More than 50% of the lesions develop on the tongue, specifically the dorsal or lateral surfaces, but they may present anywhere in the oral mucosa.7 Traumatic ulcerative granuloma with stromal eosinophilia is a fast-growing lesion, typically developing in days to weeks. Although it spontaneously regresses, the lesion may take weeks or months to resolve. In one case, it resolved 1 year later.1 Traumatic ulcerative granuloma with stromal eosinophilia has a bimodal age distribution, generally appearing in the first 2 years of life and later in the fifth through seventh decades. The male-to-female predominance is equal.1,7,11 Reoccurrence is rare, but some reports have shown patients with multiple episodes of TUGSE.13,14
Differential Diagnosis
The clinical differential diagnosis for TUGSE includes squamous cell carcinoma, pyogenic granuloma, lymphoproliferative disorder, traumatic neuroma, Langerhans cell histiocytosis, granulomatous disorders, and oral lymphoma. Inflammatory disorders such as syphilis, Behçet’s disease, herpes, histoplasmosis, Wegener granulomatosis, and others also should be considered.
Immunohistochemistry
Immunohistochemical analysis of TUGSE lesions recently has revealed the presence of CD30+ cells. These cells are associated with cutaneous lymphoproliferative disorders including LyP, anaplastic large cell lymphoma (ALCL), and borderline CD30+ lesions, among others. Systemic diseases with CD30+ cells include mycosis fungoides, other T-cell lymphomas, and Hodgkin lymphoma.15,16 Once CD30+ cells were recognized, multiple authors began speculating there was a correlation between TUGSE and the CD30+ lymphoproliferative disorders.1,2,13 Anaplastic large cell lymphoma and LyP of the oral mucosa have been reported in several cases.17-20 One report described 2 cases of ulcerated CD30+ T-cell non-Hodgkin lymphoma of the oral mucosa, one of which showed eosinophilic infiltrates and was initially thought to be TUGSE. Based on these overlapping clinical and histologic features, the authors hypothesized there was a correlation between oral ALCL, LyP, and TUGSE.17 In one report, a patient developed multiple TUGSE lesions throughout his life, suggesting a pathologic process similar to LyP. The lesion biopsied showed that 70% of the T cells expressed CD30 (Ki-1) antigen.13
Underlying Causes
In support of an underlying immunologic process that augments the growth of these lesions, 2 separate case reports of TUGSE in the presence of human T-lymphotropic virus 1 (HTLV-1) and Epstein-Barr virus have been documented.2,21 Concurrent presentation of TUGSE and HTLV-1 in one report demonstrated eosinophilia in both the oral lesion and peripheral blood, suggesting an immunologic relationship. Furthermore, the authors postulated that local trauma initiated the development of TUGSE, providing the catalyst for the HTLV-1 carrier to develop peripheral eosinophilia.21
In the second case, a 12-year-old boy developed TUGSE in the presence of Epstein-Barr virus.2 Immunologically, this virus can be reactivated from its latent stage during immunosuppression. Epstein-Barr virus has been implicated in lymphoproliferative diseases of both B- and T-cell origin, including CD30+ ALCL and LyP.22,23 The authors in this report again hypothesized there was a correlation between lymphoproliferative disorders and TUGSE lesions.2,24
Alternatively, TUGSE may simply be a reactive process to trauma or another underlying trigger. It has been speculated that the presence of eosinophils correlates with antigen insertion into the oral mucosa, whereas other ulcers of the oral mucosa are devoid of eosinophils.1 These antigens may include microorganisms, endogenous degradation products, or foreign proteins.7,25 Additionally, the presence of CD30+ lymphocytes is not isolated to lymphoproliferative disorders. CD30+ cells have been documented in arthropod bite reactions, atopic dermatitis, drug reactions, molluscum contagiosum, and scabies, among others.1,26
Healing and Management
The length of healing in TUGSE ulcers has substantial variability, from days to up to 1 year in an isolated case.1,24 Sequential expression of transforming growth factor (TGF) α and TGF-β expressed by tissue eosinophils may be underlying factors associated with a quicker healing response as demonstrated by similar ulcers in hamsters.27 Chronic nonhealing oral ulcers, particularly TUGSE lesions that demonstrated the typical increase in eosinophils in 11 of 12 cases, showed minimal TGF-α or TGF-β expression by eosinophils, perhaps indicating a possible mechanism leading to delayed wound healing in some cases. Interestingly, incisional biopsies often led to rapid wound healing, suggesting that the biopsy itself allowed for a transition back to the regular wound-healing processes.28
Traumatic ulcerative granuloma with stromal eosinophilia spontaneously resolves on its own in most cases; however, because of the concern for malignancy, it has the potential to be overtreated.26 Symptomatic treatment only is the mainstay of therapy. The patient should be instructed to avoid trauma, and referral to a dental professional is indicated when associated with dentures or other periprosthetic devices. Diet should consist of soft foods while avoiding spicy foods. Topical or oral analgesics may be necessary if substantial pain is associated with the lesion.2 Oral prednisolone was used in a patient with concurrent HTLV-1 and TUGSE to treat peripheral eosinophilia.21 The patient’s peripheral eosinophils dropped to 1% in 1 day, and the patient’s oral lesion began to improve at day 3 and disappeared by day 10. Although TUGSE may spontaneously resolve within a 10-day period without steroids, it may be a reasonable treatment to improve healing time in an otherwise healthy individual.21,26 If there is concern for malignancy, the patient should have the lesion biopsied to provide reassurance and for the added benefit of a transition to normal healing response and decreased healing time.28
Clinical Recognition
The clinician should be aware of the possibility of a CD30+ lymphoproliferative disorder, which has been associated with TUGSE in some cases, or may simulate TUGSE both clinically and histologically. Further studies are needed to clarify the relationship between these 2 entities. Whether it is a true relationship, simple coincidence, or simply overlapping clinical and histologic features remains to be determined.
- Hirshberg A, Amariglio N, Akrish S, et al. Traumatic ulcerative granuloma with stromal eosinophilia: reactive lesion of the oral mucosa. Am J Clin Pathol. 2006;126:522-529.
- Abdel-Naser MB, Tsatsou F, Hippe S, et al. Oral eosinophilic ulcer, an Epstein-Barr virus-associated CD30+ lymphoproliferation? [published online April 5, 2011]. Dermatology. 2011;222:113-118.
- Fonseca FP, Benevenuto de Andrade BA, Coletta RD, et al. Clinicopathological and immunohistochemical analysis of 19 cases of oral eosinophilic ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115:532-540.
- Alobeid B, Pan LX, Milligan L, et al. Eosinophil-rich CD30+ lymphoproliferative disorder of the oral mucosa. Am J Clin Pathol. 2004;121:43-50.
- Hjorting-Hansen E, Schmidt H. Ulcerated granuloma eosinophilicum diutinum of the tongue. report of a case. Acta Derm Venereol. 1961;41:235-239.
- Velez A, Alamillos FJ, Dean A, et al. Eosinophilic ulcer of the oral mucosa: report of a recurrent case on the tongue. Clin Exp Dermatol. 1997;22:154-156.
- Elzay RP. Traumatic ulcerative granuloma with stromal eosinophilia (Riga-Fede’s disease and traumatic eosinophilic granuloma). Oral Surg Oral Med Oral Pathol. 1983;55:497-506.
- Val-Bernal JF, Gonzalez-Vela MC, Sanchez-Santolino S, et al. Localized eosinophilic (Langerhans’ cell) granuloma of the lower lip. a lesion that may cause diagnostic error. J Cutan Pathol. 2009;36:1109-1113.
- Shapiro L, Juhlin EA. Eosinophilic ulcer of the tongue report of two cases and review of the literature. Dermatologica. 1970;140:242-250.
- Amberg S. Sublingual growth in infants. Am J Med Sci. 1902;126:257-269.
- EI-Mofty SK, Swanson PE, Wick MR, et al. Eosinophilic ulcer of the oral mucosa: report of 38 new cases with immunohistochemical observations. Oral Surg Oral Med Oral Pathol. 1993;75:716-722.
- Regezi JA, Zarbo RJ, Daniels TE, et al. Oral traumatic granuloma: characterization of the cellular infiltrate. Oral Surg Oral Med Oral Pathol. 1993;75:723-727.
- Ficarra G, Prignano F, Romagnoli P. Traumatic eosinophilic granuloma of the oral mucosa: a CD30+ (Ki-1) lymphoproliferative disorder? Oral Oncol. 1997;33:375-379.
- Doyle JL, Geary W, Baden E. Eosinophilic ulcer. J Oral Maxillofac Surg. 1989;47:349-352.
- Liu HL, Hoppe RT, Kohler S, et al. CD30+ cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol. 2003;49:1049-1058.
- Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985;66:848-858.
- Rosenberg A, Biesma DH, Sie-Go DMDS, et al. Primary extranodal CD30-positive T-cell non-Hodgkin’s lymphoma of the oral mucosa. report of two cases. Int J Oral Maxillofac Surg. 1996;25:57-59.
- Kato N, Tomita Y, Yoshida K, et al. Involvement of the tongue by lymphomatoid papulosis. Am J Dermatopathol. 1998;20:522-526.
- Savarrio L, Gibson J, Dunlop DJ, et al. Spontaneous regression of an anaplastic large cell lymphoma in the oral cavity: first reported case and review of the literature. Oral Oncol. 1999;35:609-613.
- Sciubba J, Said-Al-Naief N, Fantasia J. Critical review of lymphomatoid papulosis of the oral cavity with case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:195-204.
- Yamazaki H, Shirasugi Y, Kajiwara H, et al. Concurrent onset of eosinophilic ulcer of the oral mucosa with peripheral eosinophilia in a human T-cell leukemia virus type I carrier. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:E43-E48.
- Dojcinov SD, Venkataram G, Raffeld M, et al. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010;34:405-417.
- Kim YC, Yang WI, Lee MG, et al. Epstein-Barr virus in CD30 anaplastic large cell lymphoma involving the skin and lymphomatoid papulosis in South Korea. Int J Dermatol. 2006;45:1312-1316.
- Pietersma F, Piriou E, van Baarle D. Immune surveillance of EBV-infected B cells and the development of non-Hodgkin lymphomas in immunocompromised patients. Leuk Lymphoma. 2008;49:1028-1041.
- Salisbury CL, Budnick SD, Li S. T cell receptor gene rearrangement and CD 30 immunoreactivity in traumatic ulcerative granuloma with stromal eosinophilia of oral cavity. Am J Clin Pathol. 2009;132:722-727.
- Marszalek A, Neska-Dlugosz I. Traumatic ulcerative granuloma with stromal eosinophilia. a case report and short literature review. Pol J Pathol. 2011;3:172-175.
- Wong DT, Donoff RB, Yang J, et al. Sequential expression of transforming growth factors alpha and beta 1 by eosinophils during cutaneous wound healing in the hamster. Am J Pathol. 1993;143:130-142.
- Elovic AE, Gallagher GT, Kabani S, et al. Lack of TGF-alpha and TGF-beta synthesis by human eosinophils in chronic oral ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:672-681.
- Hirshberg A, Amariglio N, Akrish S, et al. Traumatic ulcerative granuloma with stromal eosinophilia: reactive lesion of the oral mucosa. Am J Clin Pathol. 2006;126:522-529.
- Abdel-Naser MB, Tsatsou F, Hippe S, et al. Oral eosinophilic ulcer, an Epstein-Barr virus-associated CD30+ lymphoproliferation? [published online April 5, 2011]. Dermatology. 2011;222:113-118.
- Fonseca FP, Benevenuto de Andrade BA, Coletta RD, et al. Clinicopathological and immunohistochemical analysis of 19 cases of oral eosinophilic ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115:532-540.
- Alobeid B, Pan LX, Milligan L, et al. Eosinophil-rich CD30+ lymphoproliferative disorder of the oral mucosa. Am J Clin Pathol. 2004;121:43-50.
- Hjorting-Hansen E, Schmidt H. Ulcerated granuloma eosinophilicum diutinum of the tongue. report of a case. Acta Derm Venereol. 1961;41:235-239.
- Velez A, Alamillos FJ, Dean A, et al. Eosinophilic ulcer of the oral mucosa: report of a recurrent case on the tongue. Clin Exp Dermatol. 1997;22:154-156.
- Elzay RP. Traumatic ulcerative granuloma with stromal eosinophilia (Riga-Fede’s disease and traumatic eosinophilic granuloma). Oral Surg Oral Med Oral Pathol. 1983;55:497-506.
- Val-Bernal JF, Gonzalez-Vela MC, Sanchez-Santolino S, et al. Localized eosinophilic (Langerhans’ cell) granuloma of the lower lip. a lesion that may cause diagnostic error. J Cutan Pathol. 2009;36:1109-1113.
- Shapiro L, Juhlin EA. Eosinophilic ulcer of the tongue report of two cases and review of the literature. Dermatologica. 1970;140:242-250.
- Amberg S. Sublingual growth in infants. Am J Med Sci. 1902;126:257-269.
- EI-Mofty SK, Swanson PE, Wick MR, et al. Eosinophilic ulcer of the oral mucosa: report of 38 new cases with immunohistochemical observations. Oral Surg Oral Med Oral Pathol. 1993;75:716-722.
- Regezi JA, Zarbo RJ, Daniels TE, et al. Oral traumatic granuloma: characterization of the cellular infiltrate. Oral Surg Oral Med Oral Pathol. 1993;75:723-727.
- Ficarra G, Prignano F, Romagnoli P. Traumatic eosinophilic granuloma of the oral mucosa: a CD30+ (Ki-1) lymphoproliferative disorder? Oral Oncol. 1997;33:375-379.
- Doyle JL, Geary W, Baden E. Eosinophilic ulcer. J Oral Maxillofac Surg. 1989;47:349-352.
- Liu HL, Hoppe RT, Kohler S, et al. CD30+ cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol. 2003;49:1049-1058.
- Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985;66:848-858.
- Rosenberg A, Biesma DH, Sie-Go DMDS, et al. Primary extranodal CD30-positive T-cell non-Hodgkin’s lymphoma of the oral mucosa. report of two cases. Int J Oral Maxillofac Surg. 1996;25:57-59.
- Kato N, Tomita Y, Yoshida K, et al. Involvement of the tongue by lymphomatoid papulosis. Am J Dermatopathol. 1998;20:522-526.
- Savarrio L, Gibson J, Dunlop DJ, et al. Spontaneous regression of an anaplastic large cell lymphoma in the oral cavity: first reported case and review of the literature. Oral Oncol. 1999;35:609-613.
- Sciubba J, Said-Al-Naief N, Fantasia J. Critical review of lymphomatoid papulosis of the oral cavity with case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:195-204.
- Yamazaki H, Shirasugi Y, Kajiwara H, et al. Concurrent onset of eosinophilic ulcer of the oral mucosa with peripheral eosinophilia in a human T-cell leukemia virus type I carrier. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:E43-E48.
- Dojcinov SD, Venkataram G, Raffeld M, et al. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010;34:405-417.
- Kim YC, Yang WI, Lee MG, et al. Epstein-Barr virus in CD30 anaplastic large cell lymphoma involving the skin and lymphomatoid papulosis in South Korea. Int J Dermatol. 2006;45:1312-1316.
- Pietersma F, Piriou E, van Baarle D. Immune surveillance of EBV-infected B cells and the development of non-Hodgkin lymphomas in immunocompromised patients. Leuk Lymphoma. 2008;49:1028-1041.
- Salisbury CL, Budnick SD, Li S. T cell receptor gene rearrangement and CD 30 immunoreactivity in traumatic ulcerative granuloma with stromal eosinophilia of oral cavity. Am J Clin Pathol. 2009;132:722-727.
- Marszalek A, Neska-Dlugosz I. Traumatic ulcerative granuloma with stromal eosinophilia. a case report and short literature review. Pol J Pathol. 2011;3:172-175.
- Wong DT, Donoff RB, Yang J, et al. Sequential expression of transforming growth factors alpha and beta 1 by eosinophils during cutaneous wound healing in the hamster. Am J Pathol. 1993;143:130-142.
- Elovic AE, Gallagher GT, Kabani S, et al. Lack of TGF-alpha and TGF-beta synthesis by human eosinophils in chronic oral ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:672-681.
Practice Points
- Immunohistochemical staining of traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) may suggest an underlying lymphoproliferative disorder.
- Early recognition of TUGSE, which often is malignant appearing, is key, with watchful waiting as the mainstay therapy.
- Adjunctive therapy for TUGSE includes prednisolone and oral analgesics.
