Traumatic Ulcerative Granuloma With Stromal Eosinophilia A Reactive Lesion of the Oral Mucosa

Transcription

1 Hematopathology / TRAUMATIC ULCERATIVE GRANULOMA Traumatic Ulcerative Granuloma With Stromal Eosinophilia A Reactive Lesion of the Oral Mucosa Abraham Hirshberg, MD, DMD, 1 Ninette Amariglio, PhD, 2 Sharon Akrish, DMD, 1 Ran Yahalom, DMD, 3 Hanna Rosenbaum, MD, 4 Elimelech Okon, MD, 5 and Ilana Kaplan, DMD 5 Key Words: Traumatic ulcer; Clinical pathology; Hematology; Eosinophilic ulcer; CD30; Anatomic pathology, head and neck; Lymphoma; Traumatic ulcerative granuloma with stromal eosinophilia DOI: /AFHA406GBT0N2Y64 Abstract Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is a benign lesion of the oral mucosa of an unclear pathogenesis. We analyzed the profile of the inflammatory infiltrate in 12 cases of TUGSE by using immunohistochemical analysis and polymerase chain reaction based repertoire analysis to detect T- and B-cell receptor gene rearrangements. The inflammatory infiltrate consisted in most cases of B and T lymphocytes, macrophages, abundant eosinophils, and large atypical cells. In 5 cases, CD30+ cells were found. Spectratyping analysis displayed a polyclonal rearrangement of the T-cell receptor γ gene in 6 cases and oligoclonality in 5 cases. Monoclonality was observed in 1 case that also fulfilled histologic criteria for lymphoma. Healing was uneventful in all cases, including the one suspected of being lymphoma, with no recurrences in more than 2 years follow-up. TUGSE can be regarded as reactive. Some cases, however, may harbor a dominant clonal T-cell population; in these cases, long-term follow-up is mandatory. Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is a chronic, benign, self-limiting lesion of the oral mucosa, manifesting as an ulcer with elevated margins. The most common location is the tongue, although other locations in the oral mucosa are possible. 1 Various terms have been used to describe TUGSE, including eosinophilic ulcer, eosinophilic granuloma of soft tissue, ulcerative eosinophilic granuloma, and traumatic ulcerative granuloma with stromal eosinophilia In infants, TUGSE is called Riga-Fede disease. 2 Histologically, TUGSEs show a diffuse polymorphic inflammatory infiltrate, rich in eosinophils, involving the superficial mucosa and the deeper muscle layer. Atypical large mononuclear cells scattered within the inflammatory infiltrate have been described in some cases, thus the term, atypical histiocytic granuloma. 11 The pathogenesis of TUGSE is controversial. Although trauma was considered to have a major role in its pathogenesis, obvious trauma could not be demonstrated in most cases. It has been suggested that TUGSE may be a CD30+ lymphoproliferative disease. 12,13 Alobeid et al 13 found T-cell monoclonality in 3 cases by using immunohistochemical and polymerase chain reaction (PCR) analysis and suggested that the oral lesions seemed to be the counterpart of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders. The aim of the present study was to analyze the phenotypic and genotypic profile of the inflammatory infiltrate of TUGSE by using immunohistochemical analysis and PCR-based repertoire analysis for T- and B-cell receptor gene rearrangements and to discuss the pathogenesis and outcome of these cases. Materials and Methods The archives of the oral pathology laboratory at the School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel, were 522 Am J Clin Pathol 2006;126: DOI: /AFHA406GBT0N2Y64

2 Hematopathology / ORIGINAL ARTICLE reviewed for TUGSE cases diagnosed between January 2000 and December Only cases with detailed clinical information (age, sex, clinical diagnosis) and follow-up information were used for the study. The diagnosis of TUGSE was based on clinical and histologic features that included the presence of an ulcer with a polymorphic inflammatory infiltrate intermixed with eosinophils. The infiltrate extends into the deeper tissues. Formalin-fixed, paraffin-embedded biopsy material from 12 TUGSE cases was included in the study. We cut 5-µm-thick sections from each case. One slide was stained with H&E to verify the diagnosis and evaluate the inflammatory infiltrate. Additional sections were mounted on charged glass slides and processed for immunohistochemical analysis, and 5 sections were submitted for PCR analysis. Immunohistochemical Analysis Table 1 lists the monoclonal antibodies used in this study. Immunohistochemical analysis was performed according to standard procedures. Briefly, sections were deparaffinized in xylene and hydrated through graded alcohols. Endogenous peroxidase activity was blocked by 3% hydrogen peroxide in methanol (10 minutes) and washed in phosphate-buffered saline. After incubation with 10% nonimmune goat serum (10 minutes) to block nonspecific binding, slides were incubated with the primary antibody for 1 hour in a moist chamber. Sections were washed in phosphate-buffered saline and incubated with biotinylated antimouse IgG (10 minutes) followed by incubation with avidin-biotin complex and horseradish peroxidase reagents (10 minutes) at room temperature. Visualization with the AEC kit (Zymed, San Francisco, CA) was followed by counterstaining with Mayer hematoxylin. PCR Studies DNA Extraction Sections, 5 µm thick, were prepared under sterile conditions. DNA was extracted by Proteinase K digestion at 55 C overnight, followed by chloroform-phenol extraction using standard protocols. Table 1 Monoclonal Antibodies Used in the Study Detection of T-Cell Receptor and Immunoglobulin Gene Rearrangement Approximately 1 to 2 µg of extracted genomic DNA was used as a template for PCR with consensus primers for the variable (V) and joining (J) regions of T-cell receptor (TCR) γ chain genes and the immunoglobulin heavy chain (IgH) gene as previously described. 14 Automated High-Resolution PCR Fragment Analysis (Spectratyping) Spectratyping allows analysis of all V and J regions of the TCRγ chain gene using 4 sets of consensus primers specific for the V regions of the TCRγ chain gene and primers specific for the J region. Spectratyping analysis of the T-cell rearrangement is an accurate, essential tool for detecting clonality and has been found to be superior to the conventional PCR reaction. The primers were labeled at the 5' end with 5-carboxyfluorescein (FAM). After amplification, the labeled PCR products were separated by using an automated sequencing system (ABI 310; Applied Biosystems, Weiterstadt, Germany). During electrophoresis, the capillary was scanned and the intensity of the fluorescent signals analyzed using Genescan Software ABI 672 (Applied Biosystems). The electrophoretic profile of PCR products demonstrates the presence of monoclonal, oligoclonal, or polyclonal populations according to the number and distribution of signal peaks. Polyclonality is represented by a Gaussian distribution of the PCR products, oligoclonality corresponds to a skewed TCR repertoire as visualized by spectratyping, and monoclonality to a single peak. In each case, the TCR repertoire was tested by 4 PCRs, and duplicate runs were performed to confirm reproducibility. Results A search of the files between 2000 and 2004 retrieved 12 cases of TUGSE. The clinical data are shown in Table 2. Most patients were older than 50 years (mean, 49.2 years), with an equal sex distribution. Patients were otherwise healthy without reported skin lesions. Antigen Target Source CD30 Activation/early differentiation antigen DAKO, Carpinteria, CA; mouse antihuman CD30 ALK Anaplastic lymphoma kinase Zymed, San Francisco, CA; rabbit, polyclonal anti-alk TIA-1 T-cell intracytoplasmic antigen Biocare Medical, Concord, CA; monoclonal antihuman TIA CD4 T-cell subset (helper) Zymed; mouse antihuman T-cell CD8 T-cell subset (cytotoxic) Zymed; mouse anti-cd8 CD3 T lymphocytes DAKO; mouse polyclonal antihuman T-cell CD20 B lymphocytes DAKO; mouse antihuman B-cell clone L26 von Willebrand factor Endothelial cells Zymed; mouse antihuman von Willebrand factor clone F8/86 CD68 Macrophages, monocytes DAKO; mouse antihuman macrophage CD8 clone PG-MA Ki-67 Proliferation marker DAKO; mouse antihuman clone MIB-1 Am J Clin Pathol 2006;126: DOI: /AFHA406GBT0N2Y64 523

3 Hirshberg et al / TRAUMATIC ULCERATIVE GRANULOMA In all patients, there was only a single lesion at the time of examination. The tongue was involved in 7 cases and the vestibule, buccal mucosa, and floor of the mouth in the remaining 5 cases. The lesions manifested mostly as chronic ulceration with rolled-up margins, usually associated with mild pain. In case 1, the lesion appeared as an exophytic mass in proximity to the margin of a denture (epulis fissuratum). Information on duration was limited to general estimations by patients and varied from several days to 1 year. Local trauma could be considered an etiologic factor in 4 cases, 2 resulting from a sharp tooth cusp and 1 from an ill-fitting denture; 1 developed following a biopsy for leukoplakia several months earlier. In the remaining 8 cases, local trauma had not been identified. Healing was uneventful in all cases, without recurrences, following excisional or incisional biopsy. Table 2 Clinical Data for 12 Patients With Traumatic Ulcerative Granuloma With Stromal Eosinophilia Histopathologic Findings All cases showed ulcerated mucosa with a dense cellular infiltrate focally involving the epithelium, extending into the deeper underlying soft tissues and between the muscle fibers Image 1. The infiltrate was composed primarily of small, round lymphocytes, granulocytes, and abundant eosinophils Image 2. In 7 cases, large atypical cells could be identified in clusters or scattered as single cells within the inflammatory infiltrate; the large cells had irregular nuclear contours, fine chromatin, small nucleoli, and abundant cytoplasm Image 3. In case 2, mitotic figures were observed in several of the large cells Image 4. Proliferating endothelial cells and blood vessels were distributed throughout the lesion. The diagnostic criteria for TUGSE were met in all cases. However, in case 2, malignant T-cell lymphoma had been suspected because of the Case No./ Size Recurrence/ Sex/Age (y) Location Duration (mm) Treatment Follow-up (y) Trauma 1/F/51 Anterior maxillary vestibule 1 y 12 Excision No/1.5 Trauma from denture 2/M/55 Tongue, dorsal Unknown 10 Excision No/2.5 None 3/F/72 Mandibular vestibule Few days 8 Excision No/4 None 4/F/67 Tongue, ventral 1 mo 5 Excision No/3 None 5/M/14 Buccal mucosa 2 mo 3 Excision No/3.5 Trauma, sharp tooth cusp 6/M/87 Floor of mouth 3-4 wk 12 Excision No/3.5 None 7/M/57 Tongue, posterior lateral Several months 13 Excision No/3 Trauma, sharp tooth cusp 8/M/52 Tongue, anterior lateral Unknown 4 Excision No/3 Following incisional biopsy for leukoplakia 9/F/36 Mandibular vestibule Several months 12 Excision No/4.5 None 10/F/44 Tongue, middle lateral Several months 15 Excision No/4 None 11/F/34 Tongue, middle lateral Several months 5 Excision No/2 None 12/M/21 Tongue, middle lateral Unknown 10 Excision No/1.5 None Image 1 Traumatic ulcerative granuloma with stromal eosinophilia. Low-power image showing ulceration with a dense inflammatory infiltrate extending deep into the muscle of the tongue (H&E, original magnification 40). Image 2 Traumatic ulcerative granuloma with stromal eosinophilia. High-power image showing the inflammatory infiltrate composed mainly of small, round lymphocytes, granulocytes, and abundant eosinophils (H&E, original magnification 200). 524 Am J Clin Pathol 2006;126: DOI: /AFHA406GBT0N2Y64

4 Hematopathology / ORIGINAL ARTICLE presence of a subpopulation of large, atypical monocytoid cells with abundant mitotic figures that focally infiltrated blood vessel walls. Immunohistochemical Findings Table 3 summarizes the immunohistochemical results. The lymphocytic infiltrate was composed primarily of a mixture of B and T lymphocytes. The T-lymphocyte population usually showed an approximately equal distribution of helper and cytotoxic cells. Prominent focal aggregates of T lymphocytes (CD3+ and T-cell intracytoplasmic antigen 1+) were noticed in most cases, whereas in case 1, these cells composed the majority of the infiltrate. CD68+ cells (macrophages) intermixed with the inflammatory Image 3 High-power image showing large cells with irregular nuclear contours, fine chromatin, small nucleoli (arrows) (H&E, original magnification 400). infiltrate were found in most cases, and von Willebrand factor was positive in blood vessel walls. Between 10% and 50% of all lymphocytes expressed the proliferation marker Ki-67 in small and large cells Image 5. Small clusters of CD30+ cells were found in 1 case (case 2). These were composed of large, atypical cells found in small aggregates infiltrating into the underlying muscle Image 6. In 4 other cases, single CD30+ cells were found scattered within the lymphoid infiltrate. Anaplastic lymphoma kinase was negative in all cases examined. Large cells were found in 7 cases, the majority were positive for T-cell markers, and none were of B-cell origin. Some but not all were CD30+. Other large cells reacted with the macrophage marker CD68. Although large, plump Image 4 (Case 2) High-power image showing mitotic figures in several of the large cells (arrows) (H&E, original magnification 400). Table 3 Immunohistochemical Results in 12 Cases of Traumatic Ulcerative Granuloma With Stromal Eosinophilia * Large T-Cell Clonality Case No. CD30 ALK TIA-1 CD4 CD8 CD3 CD20 vwf CD68 Ki-67 Cells Eosinophils Spectratyping 1 Positive (scattered) Oligoclonal 2 Positive (aggregates) Monoclonal 3 Positive (scattered) Oligoclonal Polyclonal Polyclonal Polyclonal 7 Positive (scattered) Oligoclonal 8 Positive (scattered) Polyclonal Oligoclonal Oligoclonal Polyclonal Polyclonal ALK, anaplastic lymphoma kinase; TIA, T-cell intracytoplasmic antigen; vwf, von Willebrand factor; +, present;, negative or absent. * The semiquantitative scale was as follows: 0, none; 1, <25%; 2, 25%-50%; 3, 50%-75%; 4, >75%. Positive in large and small cells. Am J Clin Pathol 2006;126: DOI: /AFHA406GBT0N2Y64 525

5 Hirshberg et al / TRAUMATIC ULCERATIVE GRANULOMA Image 5 K-67 labeled section showing labeling of about 50% of the cells (original magnification 200). A B ,600 1, Image 7 A, Gaussian distribution of polymerase chain reaction (PCR) products of rearranged T-cell receptor γ genes indicates the presence of a polyclonal T-cell population. B, Skewed distribution of the PCR products indicates the presence of an oligoclonal T-cell population. C, A dominant peak of PCR products indicating the presence of a monoclonal T-cell population. C Image 6 CD30-labeled section showing clusters of CD30+ cells extending into the underlying muscle (original magnification 400). endothelial cells positive for von Willebrand factor were found in the vessel walls, none of the scattered large cells within the infiltrate reacted with this antibody. Spectratyping Analysis Six cases displayed a Gaussian distribution of the PCR products indicating a polyclonal rearrangement of the TCRγ genes Image 7. Skewing of the distribution, which indicates oligoclonality, was found in 5 cases; in these cases, there were between 2 and 6 dominant peaks per PCR product (8-14 peaks per case for the 4 PCRs). Monoclonality was observed in only 1 case (case 2), which corresponded to the case microscopically suspected of being lymphoma (Table 3). Analysis of the immunoglobulin gene rearrangement disclosed a polyclonal distribution in all cases. Follow-up Recurrences or new lesions were not reported in any of the cases within a follow-up period of 1.5 to 4.5 years. The patient diagnosed with lymphoma also had no sign of local recurrence or new lesions. Monoclonality for T-cell rearrangement was not found in bone marrow aspirate and biopsy specimens or in his peripheral blood specimen. The patient is still being monitored closely more than 2 years after removal of the tongue lesion, with long-term follow-up planned. Discussion TUGSE is an obscure lesion that affects the oral mucosa. The most frequent clinical manifestation is that of an ulcer, 526 Am J Clin Pathol 2006;126: DOI: /AFHA406GBT0N2Y64

6 Hematopathology / ORIGINAL ARTICLE often with rolled borders, which mimics squamous cell carcinoma. The duration of TUGSE varies, ranging from several weeks to several months and even up to 1 year (1 case in the present series). Microscopically, TUGSE is characterized by a dense polymorphic inflammatory infiltrate extending into the underlying muscle. The dominant cell types in the inflammatory infiltrate are small lymphocytes, with abundant eosinophils. In the present study, B and T lymphocytes were found in all cases. Focal aggregates of T lymphocytes were common in most cases; in case 1, T cells dominated for an unclear reason. The presence of eosinophils is not completely understood because most traumatic oral ulcers are devoid of eosinophils. It has been suggested that eosinophils represent a tissue reaction to some unknown antigen introduced via mucosal breakdown following trauma. 2 Mucosal degeneration so characteristic of TUGSE may be attributed to proliferation of cytotoxic T cells or toxic products released by degranulating eosinophils. Aggregates of T-cell intracytoplasmic antigen 1+ cells, a marker of cytolytic T cells, were found in large quantities in all cases in the present study, supporting the role of cytotoxic T cells in the pathogenesis of TUGSE. Eosinophils have been found to generate a wide spectrum of inflammatory and regulatory cytokines ; some of these, such as tumor necrosis factor, can enhance tissue damage. In most of their TUGSE cases, Elovic et al 20 showed a lack of significant synthesis of transforming growth factor by eosinophils, which can explain the delayed healing characteristic of TUGSE. The presence of large, atypical mononuclear cells is another microscopic feature of TUGSE present in most cases (58% in the present study). The origin of these large cells has been a matter of debate. Regezi et al, 8 in a study of 8 cases, detected the macrophage marker CD68 or the dendrocyte marker factor XIIIa. El-Mofty et al, 7 however, in a series of 38 cases, found that the atypical large cells were positive only for vimentin, suggesting that they represent myofibroblasts. It has been suggested that TUGSE may be a CD30+ lymphoproliferative disorder. 12,13 CD30 is a transmembrane glycoprotein with an extracellular domain homologous to the tumor necrosis factor/nerve growth factor receptor superfamily, originally described as a surface molecule recognized by the Ki-1 monoclonal antibody on Reed-Sternberg cells. 21 CD30 is commonly expressed on activated B and T cells. Certain lymphoproliferative disorders express the CD30 antigen. The spectrum of CD30+ cutaneous lymphoproliferative disorders includes lymphomatoid papulosis, primary cutaneous anaplastic large cell lymphoma, and borderline CD30 lesions. 22,23 The involvement of the oral cavity with lymphoproliferative disorders, although rare, has been reported, but the literature is somewhat confusing, and definite comparison is difficult because CD30 was not evaluated in these studies. Ficarra et al 12 were the first to report a case in which CD30+ cells were found in an ulcerated lesion histologically resembling TUGSE. The patient had multiple episodes of recurrent, self-healing eosinophilic ulcers in the oral mucosa. It was suggested that TUGSE of the oral mucosa may represent the oral counterpart of cutaneous CD30+ lymphoproliferative disorder. Alobeid et al 13 recently described 3 patients with oral TUGSE containing CD30+ atypical cells in which T- cell clonality was demonstrated by using PCR analysis of the TCRγ chain gene. In 1 case, the lesion healed completely following incisional biopsy; in the other 2 cases, additional selfhealing oral and extraoral lesions developed. Contrary to the findings of Ficarra et al, 12 Alobeid et al 13 believed that the lesions they reported represented a subset of cases of TUGSE that share common features with primary cutaneous CD30+ lymphoproliferative disorders. CD30 expression also has been found in nonneoplastic disorders, such as atopic dermatitis, 27 drug reactions, 28,29 scabies, 30 and molluscum contagiosum. 31 Cepeda et al 32 demonstrated the presence of CD30+ lymphoid cells in 70% of a group of common nonneoplastic cutaneous conditions rich in neutrophils and eosinophils. All cases studied were polyclonal for TCR rearrangements. Of the 28 cases, 5 cases were insect bites, 4 of which contained CD30+ cells. Their study indicates that CD30+ cells are a component of a reactive rather than a neoplastic process. In the present study, clusters of CD30+ cells were identified in 1 case and scattered, single CD30+ cells were found in 4 other cases. In the absence of additional clinical and histologic support, a diagnosis of lymphoproliferative disorder cannot be established. The fact that anaplastic lymphoma kinase, a marker associated with large cell CD30+ lymphoma, was negative in all cases in the present study further supports the reactive nature of TUGSE. The presence of a dense, lymphoid infiltrate in a lesion may raise suspicions of lymphoid malignancy. Several benign reactive lesions containing a significant lymphoid component that may demonstrate histologic atypia should be considered in the differential diagnosis, such as angiolymphoid hyperplasia with eosinophilia, atypical histiocytic granuloma, and lymphomatoid papulosis. 26,33-38 A careful search for other characteristics of malignant lymphoma should always be performed to aid in differentiating true malignant lymphoma from reactive benign lesions, such as abundant atypical cells infiltrate, significant mitotic activity, and infiltration into blood vessel walls. In some cases, however, the diagnosis may be difficult to reach with confidence on the basis of histologic and immunohistochemical findings alone. Low-grade lymphoma, for example, may only be recognized retrospectively, when lesions recur several times, spread to other areas, or develop more pronounced malignant features microscopically. In the present study, case 2, in addition to features of TUGSE, fulfilled many histologic criteria for lymphoma. Am J Clin Pathol 2006;126: DOI: /AFHA406GBT0N2Y64 527

7 Hirshberg et al / TRAUMATIC ULCERATIVE GRANULOMA Spectratyping analysis of this case demonstrated clonal rearrangement of TCRγ genes, supporting the diagnosis of T- cell lymphoma. The lesion had healed nicely by the time the molecular workup was completed, and no recurrence or lesions at other organs were found in more than 2 years of follow-up. Detection of a dominant clone of a T-cell population as a single criterion in a lymphoproliferative process is insufficient to diagnose a T-cell lymphoma. Because spontaneous regression of T-cell lymphoma is a recognized phenomenon, 39 the question of the true nature of the lesion in this particular case cannot be resolved. Nevertheless, in the presence of monoclonality, a lymphoma workup should always be undertaken, and lifelong follow-up is mandatory. For the other cases analyzed in the present series, polyclonality was present in 6 cases and oligoclonality in 5 cases, an indication of their reactive nature. Based on the present study and information in the literature, TUGSE is self-limiting and rarely recurs. In the absence of alarming histologic findings, a follow-up period of 1 or 2 years seems adequate. In the present study, the phenotypic and genotypic profile of TUGSE was characterized. It can be suggested that most cases of TUGSE are reactive; some, however, may harbor a dominant clonal T-cell population. Atypical histologic findings in addition to the presence of monoclonality can serve as a warning sign for a malignant lymphoid proliferation. The question of whether monoclonality indicates a true T-cell lymphoma of low-grade malignancy or a variant of a reactive lymphoproliferative process to some unknown stimulus has not been resolved. From the 1 Department of Oral Pathology and Oral Medicine, Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel; 2 Laboratory of Hematology and Molecular Biology and 3 Department of Oral and Maxillofacial Surgery, Sheba Medical Center, Tel-Hashomer, Israel; 4 Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center and Bruce Rappaport Faculty of Medicine, Haifa, Israel; and 5 Institute of Pathology, Rabin Medical Center, Bellinson Campus, Petah-Tiqva, Israel. Address reprint requests to Dr Hirshberg: Dept of Oral Pathology and Oral Medicine, Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel. References 1. Bhaskar SN, Lilly GE. Traumatic granuloma of the tongue (human and experimental). Oral Surg Oral Med Oral Pathol. 1964;18: Elzay RP. Traumatic ulcerative granuloma with stromal eosinophilia (Riga-Fede disease and traumatic eosinophilic granuloma). Oral Surg Oral Med Oral Pathol. 1983;55: Sklavounou A, Laskaris G. Eosinophilic ulcer of the oral mucosa. Oral Surg Oral Med Oral Pathol. 1984;58: Tang TT, Glicklich M, Hodach AE, et al. Ulcerative eosinophilic granuloma of the tongue: a light and electronmicroscopy study. Am J Clin Pathol. 1981;75: Doyle JL, Geary W, Baden E. Eosinophilic ulcer. J Oral Maxillofac Surg. 1989;47: Lombardi T, Kuffer R, Samson J. Eosinophilic ulceration of the oral mucosa: a case report. Int J Oral Maxillofac Surg. 1993;22: 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: Regezi JA, Zarbo RJ, Daniels TE, et al. Oral traumatic granuloma: characterization of the cellular infiltrate. Oral Surg Oral Med Oral Pathol. 1993;75: Mezei MM, Tron VA, Stewart WD, et al. Eosinophilic ulcer of the oral mucosa. J Am Acad Dermatol. 1995;33: Movassaghi K, Goldman ML, Keith D. Ulcerative eosinophilic granuloma: a report of five new cases. Br J Oral Maxillofac Surg. 1996;34: Eversole LR, Leider AS, Jacobson PL, et al. Atypical histiocytic granuloma. Cancer. 1985;55: Ficarra G, Prignano F, Romagnoli P. Traumatic eosinophilic granuloma of the oral mucosa: a CD30+ (Ki-1) lymphoproliferative disorder? Oral Oncol. 1997;33: Alobeid B, Pan LX, Milligan L, et al. Eosinophil-rich CD30+ lymphoproliferative disorder of the oral mucosa. Am J Clin Pathol. 2004;121: Wood GS, Tung RM, Haeffner AC, et al. Detection of clonal T-cell receptor gamma gene rearrangements in early mycosis fungoides/sézary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). J Invest Dermatol. 1994;103: Munitz A, Levi-Schaffer F. Eosinophils: new roles for old cells. Allergy. 2004;59: Straumann A, Simon HU. The physiological and pathophysiological roles of eosinophils in the gastrointestinal tract. Allergy. 2004;59: Hirashima M, Ueno M, Kamiya K, et al. Functional heterogeneity of human eosinophil chemotactic lymphokines. Lymphokine Cytokine Res. 1991;10: Moqbel R, Levi-Schaffer F, Kay AB. Cytokine generation by eosinophils. J Allergy Clin Immunol. 1994;94: Schmid-Grendelmeier P, Altznauer F, Fischer B, et al. Eosinophils express functional IL-13 in eosinophilic inflammatory diseases. J Immunol. 2002;169: Elovic AE, Gallagher GT, Kabani S, et al. Lack of TGF-α and TGF-β synthesis by human eosinophils in chronic oral ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81: Schwab U, Stein H, Gerdes J, et al. Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin s disease and a subset of normal lymphoid cells. Nature. 1982;299: Ralfkiaer E, Delsol G, Willemze R, et al. Primary cutaneous CD30-positive T-cell lymphoproliferative disorders. In: Jaffe ES, Harris NL, Stein H, et al, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001: World Health Organization Classification of Tumours. 23. 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: Am J Clin Pathol 2006;126: DOI: /AFHA406GBT0N2Y64

8 Hematopathology / ORIGINAL ARTICLE 24. Tomich CE, Shafer WG. Lymphoproliferative disease of the hard palate: a clinicopathologic entity: a study of 21 cases. Oral Surg Oral Med Oral Pathol. 1975;39: Wright JM, Dunsworth AR. Follicular lymphoid hyperplasia of the hard palate: a benign lymphoproliferative process. Oral Surg Oral Med Oral Pathol. 1983;55: Eversole LR, Leider AS, Jacobson PL, et al. Atypical histiocytic granuloma: light microscopic, ultrastructural and histochemical findings in an unusual pseudomalignant reactive lesion of the oral cavity. Cancer. 1985;55: Piletta PA, Wirth S, Hommel L, et al. Circulating skinhoming T cells in atopic dermatitis: selective up-regulation of HLA-DR, interleukin-2r, and CD30 and decrease after combined UV-A and UV-B phototherapy. Arch Dermatol. 1996;132: Nathan DL, Belsito DV. Carbamazepine-induced pseudolymphoma with CD-30 positive cells. J Am Acad Dermatol. 1998;38: Saeed SA, Bazza M, Zaman M, et al. Cefuroxime induced lymphomatoid hypersensitivity reaction. Postgrad Med J. 2000;76: McCalmont TH, LeBoit PE. A lymphomatoid papule, but not lymphomatoid papulosis! Am J Dermatopathol. 2000;22: Guitart J, Hurt MA. Pleomorphic T-cell infiltrate associated with molluscum contagiosum. Am J Dermatopathol. 1999;21: Cepeda LT, Pieretti M, Chapman SF, et al. CD30-positive atypical cells in common non-neoplastic cutaneous infiltrates rich in neutrophils and eosinophils. Am J Surg Pathol. 2003;27: Crimwood R, Sweinhart JM, Aeling JL. Angiolymphoid hyperplasia with eosinophilia. Arch Dermatol. 1979;115: Buckerfield JB, Edwards MB. Angiolymphoid hyperplasia with eosinophilia in oral mucosa. Oral Surg Oral Med Oral Pathol. 1979;47: Eveson JW, Lucas RB. Angiolymphoid hyperplasia with eosinophilia. J Oral Pathol Med. 1979;8: Buchner A, Silverman S Jr, Wara WW, et al. Angiolymphoid hyperplasia with eosinophilia (Kimura s disease). Oral Surg Oral Med Oral Pathol. 1980;49: Peters E, Altini M, Kola AH. Oral angiolymphoid hyperplasia with eosinophilia. Oral Surg Oral Med Oral Pathol. 1986;61: de Vicente Rodriguez JC, Santosoler JM, Gutierrez LM, et al. Atypical histiocytic granuloma of the tongue: case report. Br J Oral Maxillofac Surg. 1991;29: 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: Am J Clin Pathol 2006;126: DOI: /AFHA406GBT0N2Y64 529