Intraoral epithelioid and spindle cell hemangioma associated with pseudoepitheliomatous hyperplasia: An immunohistochemical study

Epithelioid hemangioma (EH) is a benign vascular tumor that frequently affects the skin and subcutaneous tissue. Clinically, EH presents as a red to violaceous papule, nodule, or plaque, measuring about 1 cm.1 Without gender predilection, EH commonly affects young adults (20–50 years), preferentially head and neck region and distal extremities, followed by trunk, bone, lung, and lymph nodes.1 Microscopy shows a benign vascular proliferation characterized by small to capillary-sized vessels lined with plump, epithelioid endothelial cells. However, the morphologic spectrum of EH is broad, including intravascular growth, cellular, or solid proliferation, as well as heavy inflammatory infiltrate.2 Interestingly, several cases of hemorrhagic epithelioid and spindle cell hemangioma have been reported,3-5 with two relevant studies suggesting that they represent an EH variant.6, 7 To date, about 36 cases of intraoral EH have been reported, with most cases affecting the lips (n = 16), followed by the tongue (n = 10) and buccal mucosa (n = 7).8-10 There is a slight male predilection (60%), frequently affecting young adults (mean age, 37 years).8 To our knowledge, intraoral EH showing pseudoepitheliomatous hyperplasia (PH) and hemorrhagic stroma permeated by florid mixed inflammatory infiltrate is an unusual finding. A 58-year-old male patient was referred, presenting an asymptomatic gingival lesion 6 months ago. The medical history was noncontributory. Moreover, no skin or other mucous membrane involvement was observed. The patient had been wearing a maxillary, removable, partial denture for about 5 years. Intraoral examination revealed a light- to dark-red, 1.5-cm diameter nodule with an irregular surface located over the buccal attached gingiva of the left maxillary canine and extending to the alveolar mucosa (Figure 1A). The periapical and panoramic radiograph exams did not show bone involvement. The clinical differential diagnosis included pyogenic granuloma, vascular malformation, and peripheral giant cell lesion. The lesion was surgically removed and surgical periodontal treatment was performed. By microscopy, at low-power magnification, an overt PH surrounding a hemorrhagic stroma and inflammatory cell infiltrate was evident. At intermediate-power view, an epithelioid to spindle cellular proliferation admixed with mixed inflammatory infiltrate (including foci of eosinophils) and isolated multinucleated giant cells were highlighted. At high-power view, there was a proliferation of small vessels lined by plump, epithelioid endothelial cells, which displayed abundant eosinophilic or amphophilic cytoplasm, nucleoli evident, sometimes vacuolated with occasional presence of red blood cells in vasoformative channels (Figure 1B–H). Atypical mitotic figures, necrosis, and nuclear pleomorphism were absent, and an HHV-8 immunomarker was negative. The diagnosis was PH-associated epithelioid and spindle cell hemangioma. Immunohistochemical analysis was carried out to characterize the prominent inflammatory cell infiltrate. CD3+ T cells were often observed, with a similar amount of CD4+ (most expressing CD25 and FOXP3, a regulatory T cell phenotype) and CD8+ T cells. CD20+ B cells were scarce; however, CD138 highlighted sheets of plasma cells. Relevantly, numerous M2-macrophages (CD68+/CD163+) were detected, as well as isolated multinucleated giant cells. CD11c distinctly highlighted this macrophage population. Infiltration by dendritic cells (DCs) was also visualized. S100+ cells were more numerous than CD1a+ and CD207+ cells (Langerhans cells). Moreover, CD123+ plasmacytoid DCs and numerous submucosal DCs (CD209+ and FXIIIa+ cells) were also detected. The Ki-67 proliferative index, which included only the analysis of epithelioid and spindle endothelial cells, was low (5%), while CD34 highlighted the epithelioid endothelial cells (Figure 2). D2-40 highlighted scarce small lymphatic vessels below the epithelium. After 2 months of follow-up, complete healing was observed (Figure 1I). The patient remains well at 9 years' follow-up. Although hemorrhagic stroma and florid inflammatory infiltrate can be observed,2 PH is an unusual finding when assessing EH, expanding its histopathological spectrum. An interesting study assessing 58 EHs subclassified them as typical (44%), cellular (36%), and angiolymphoid hyperplasia with eosinophilia (ALHE) (20%) variants.2 While the differential diagnosis for cellular EH includes malignant epithelioid vascular tumors (such as epithelioid hemangioendothelioma and angiosarcoma), that for ALHE includes inflammatory conditions, mainly Kimura disease.2 Of note, in this same study, most head and neck EHs (75%) showed a prominent inflammatory infiltrate. Despite this, the present case did not meet the criteria for ALHE-variant EH. In fact, prominent lymphoid follicles, evident eosinophilic infiltration, and damaged medium-sized vessels, typical ALHE findings, were not observed. Moreover, in the current case, bone involvement was not observed. This distinction is critical, given the anatomy of periodontal tissues, as it is known that intraosseous EH can be multifocal and follows an aggressive clinical presentation.2, 6 Interestingly, several cases of hemorrhagic epithelioid and spindle cell hemangioma, typically affecting acral bones, some of them with multifocal involvement, and initially suggesting either angiosarcoma or epithelioid haemangioendothelioma, have been reported.3-5 Microscopically, these cases showed epithelioid and spindle endothelial cells in an evident lobular pattern of growth, delineating compressed, slit-like vascular spaces, and associated with abundant extravasated red blood cells. Relevantly, two studies assessing 50 EHs of bone6 and 18 epithelioid and spindle cell hemangiomas of bone and/or soft tissue7 believe that hemorrhagic epithelioid and spindle cell hemangioma in fact represents an EH variant. In these studies, some cases contained a prominent inflammatory infiltrate and variable proportions of spindle cell areas,6, 7 as well as scattered osteoclast-type giant cells,6 as in the current case. The etiology of EH is still unclear, but several studies suggest a neoplastic nature in an EH subset, supported by recurrent cytogenetic abnormalities involving the FOS and FOSB genes, in about one-third of EHs, preferentially in bone and penis, presenting cellular variants or atypical histopathologic features.1, 2, 7, 11 Moreover, a recent study describes a novel GATA6–FOXO1 fusion detected in 5 of 28 (18%) EH cases, with predilection for skin and head and neck region.12 Of note, these genetic abnormalities have not been reported in the ALHE variant, suggesting that other mechanisms, perhaps reactive or inflammatory in nature, distinct from gene rearrangements, should also be considered in the pathogenesis of the EH subset.2, 8 In the current case, the use of a maxillary removable partial denture could suggest trauma; however, it presented an adequate state of conservation and adaptation. In addition, optimal oral hygiene was observed. The PH is a microscopical finding extremely rare in EH.7 In the current case, although uncommon in the oral cavity, angiokeratoma, epithelioid angiomatous nodule (EAN), and spindle cell hemangioma (SCH) should be included in the differential diagnosis.13-17 Unlike EH, angiokeratoma shows hyperkeratosis, acanthosis and papillomatosis surrounding large, dilated, and congested blood vessels lined by normal-appearing endothelium and containing organized thrombi.13, 14 EAN is characterized by a solid and circumscribed proliferation of epithelioid endothelial cells, often without inflammation, allowing its distinction from EH.15, 16 SCH shows ectatic, thin-walled vessels lined by flat endothelial cells (cavernous hemangioma-like area) intermixed with more cellular areas, of bland spindled and epithelioid cells (Kaposi-sarcoma-like area).17 Immunohistochemical studies assessing EHs have focused on analyses of vascular and stromal markers.1, 7, 12 Here, we show a detailed analysis of the inflammatory component, evidencing a heterogeneous immune cell population, which may help to better understand the pathogenesis of EH with an exuberant inflammatory component. Treatment of oral EH is by surgical excision, and prognosis is usually good, as in the present case. In cutaneous EH, other therapeutic approaches, including diathermy, laser cauterization, cryotherapy, intralesional corticosteroids, oral retinoids, and pentoxifylline, have also been reported.8 Jorge Esquiche León has received research Grants (2016/11419-0, 2022/07479-9, and 2022/12760-9) from the State of São Paulo Research Foundation (FAPESP) and research Grant (304241/2021-0) from National Council for Scientific and Technological Development (CNPq). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. The authors declare no conflict of interest. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in this study. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.