Pleomorphic Adenoma and Trauma: a Case Report With Rare Clinical Presentation

Background Pleomorphic adenoma (PA) is the most common benign salivary gland tumor. Many factors have been implicated in the etiology of PA, one of which is genetic alteration in PLAG1 and HMGA2 genes. Few cases were reported about PAs appearing in patients with of or denture wear. with revealed and


Background
Salivary gland tumors are a group of rare heterogeneous lesions with complex clinical and histological features accounting for about 3-5% of all head and neck neoplasms. [1] Pleomorphic adenoma (PA), a benign mixed tumor, is considered the most prevalent salivary gland neoplasm constituting about 60% of all benign salivary gland tumors. [2,3] The most common locations for PAs are the parotid glands (60-73%), followed by submandibular and minor salivary glands (40-60%). [4] Among minor salivary glands, the most frequently affected site is the palate (42.8-68.8%) and upper lip (10%) with other rare intraoral locations reported such as the oropharynx (2.5%) and retromolar trigone (0.7 %). [5] PAs have a female predilection with an average age ranging from 43 to 46-years-old. [6,7] It is considered one of the few benign lesions that can undergo malignant transformation; changing into carcinoma (CXPA-Carcinoma ex pleomorphic adenoma) with 6% aggressive progression rate, [8] following multiple genetic alterations that are still not fully clear. [9,10] The risk increases as the age of the patient, duration and size of the lesion increase. [3,6] Little is known about the etiology of PAs in terms of onset, progression, chromosomal alterations, and gene mutations detected. Some alterations were suggested by previous cytogenetic studies that revealed characteristic processes of recurrent translocations and intrachromosomal rearrangement that consequently lead to speci c gene fusion that involves certain transcription factor genes namely: PLAG1 and HMGA2. [11,12] However, some other factors have been implicated such as exposure to head and neck irradiation, oncogenic simian virus (SV40) and excessive use of tobacco and their products. [3,6] To date, very few case reports have recorded intraoral PA associated with a previous history of trauma, injuries, or ill-tting dentures. The following case-report is an oral PA located in the upper left labial vestibule, clinically resembling a typical denture ssuratum.

Case Presentation
A 73-year-old female presented to the Oral Medicine Department complaining of a painless exophytic mass located on the upper left labial vestibule, which started two months ago and increased in size over time. The patient reported wearing a maxillary complete denture all day and during sleep for 15 years.
The denture was not professionally modi ed or relined all over this period.
Upon medical history taking, the patient reported being on oral hypertensive drugs for years. No speci c ndings were noted on extra oral examination, while intraoral examination revealed a rm, pink, leaf-like exophytic mass measuring 1 by 1 cm in the upper left labial vestibule (upper lateral/ canine region).
( Fig. 1, 2) The mass had normal consistency, smooth surface texture and was surrounded by normal oral mucosa. No other abnormal ndings were found elsewhere in the oral cavity.
The initial differential diagnosis included denture ssuratum (because of the long-term use of the denture and the typical leaf-like clinical appearance) and irritational broma (that could be due to irritation from the denture upper ange). An excisional biopsy was performed, and it revealed a capsulated submucosal mass ( Fig. 3) that was taken for histopathological examination to help in reaching a conclusive nal diagnosis. Two independent pathologists reviewed the hematoxylin and eosin stained specimens (Fig. 4), and to con rm the diagnosis, immunohistochemical staining was performed (

Management
Histopathological results suggested the diagnosis of PA and since the recommended approach for managing intraoral minor salivary gland neoplasms that lack malignant features is conservative complete surgical excision with tumor-free margins, [13] and as excisional biopsy was already performed, no further interventions were needed. However, since previous studies concluded general di culty in complete surgical removal of salivary gland PA, which leads to a 4.6% rst recurrence rate, [10] the patient was called for follow up after three months. (Fig. 6) In addition, the patient was advised to stop wearing the denture for two weeks and was instructed about proper denture-hygiene measures. After one year, the patient reported that the lesion healed completely with no evidence of recurrence.

Discussion And Conclusion
PAs usually present as painless, well delimited masses frequently arising in major salivary glands with uncommon occurrence in minor salivary glands primarily involving the palate followed by upper lip and buccal mucosa. [14][15][16][17] When occurring in the upper lip, they usually manifest as mobile, submucosal nodular masses with partial or no capsules. [14] The presented case shows a PA that resembles a denture ssuratum, with a typical leaf-like appearance, in the upper labial mucosa. Clinical examination suggested a differential diagnosis of denture ssuratum followed by irritational broma that would classically be surgically excised to allow proper t of the denture. To reach a de nitive diagnosis, an excisional biopsy was performed that revealed a wellencapsulated nodular mass making the diagnosis of both denture ssuratum and irritational broma less probable. Histopathological examination revealed a well encapsulated mass showing proliferating glandular epithelial cells exhibiting architectural diversity which is a characteristic feature for PA. The proliferating glandular cells were formed mainly of ductal and myoepithelial cells. Numerous duct-like structures showing pinked eosinophilic stroma were detected, con rming a nal diagnosis of PA. Since PAs are benign epithelial neoplasms demonstrating both epithelial and modi ed myoepithelial differentiation with diversi ed histologic features, immunoexpression of different immunomarkers (CK7, P63, SMA, CD117) were investigated. Our results were consistent with other data reported in literature. [18,19] The tumor cells showed positive immunosignals to Ck7,SMA. Furthermore, p63 immunohistochemistry staining was detected and it was evident as nuclear expression. On the other hand, CD117 immunohistochemistry staining revealed weak positive cytoplasmic staining in very few ductal epithelial cells, excluding the diagnosis of adenoid cystic carcinoma, which is consistent with other studies showing similar results regarding CD117 expression in Pas. [20,21] Since excisional biopsy was already performed, no further invasive interventions were intended.
To date, very few cases of PAs arising intraorally in different places were associated with a history of trauma or denture-wear. Fatahzadeh [15] reported a case of upper lip PA with an onset related to a lip trauma that occurred 25 years ago. This is in addition to a case reported by Singh et al. [22] of a male patient having an upper labial PA with a history of trauma 7 years earlier in the same location, and another case of a female patient reporting a history of trauma 8 years ago before developing a PA on the upper right side of the lip. [23] Only two case reports were recorded by Jiménez [24] and Dyalram et al. [25] for patients wearing maxillary dentures where PAs developed on the hard palate and upper labial sulcus, respectively. However, the denture status in terms of tting, stability, and duration of wearing the dentures were not stated.
Several previous studies already suggested that Chronic Mechanical Irritation (CMI) caused by intraoral injury-causing agents such as ill-tting dentures (including those with sharp surfaces, defective retention or stability and overextended anges) can trigger changes in healthy oral mucosa, intensify an existing oral disease and even play a role as a tumor promotor. [26,27] In a recent study conducted on oral mucosal epithelial cells and broblasts, mechanical stress was found to in uence a signi cant increase in in ammatory cytokines Interleukin 6 and Interleukin 8 (IL-6 and IL-8) production. It also demonstrated that high stress levels induced production of Fibroblast Growth Factor (FGF-2) and Epidermal Growth Factor (EGF) as means of cellular defense mechanism. [28] A meta-analysis showed that chronic trauma was linked to carcinogenesis in several mechanisms including increased mitosis, DNA alteration and chemical mediators/oxidative stress release; which contributes to further DNA damage. [29] Additionally, there was an increased risk of cancer development in denture users, with an elevated likelihood for ill-tting dentures, which could suggest a similar correlation between denture wearing and tumor development (including salivary gland tumors).
[30] Nevertheless, to date, there is not enough evidence that links denture use or CMI to development of Salivary gland tumors including PAs.
Limitations of the presented case include improper testing of the denture stability/ t, denture hygiene and inability to recall the patient for a clinical follow-up due to the total lockdown measures during the COVID- To conclude, this case suggests a relation between trauma and development of salivary gland tumors including PAs. Based on the role of CMI in tumorigenesis, DNA alteration and oxidative stress release which advocates a contribution to genetic alterations responsible for PA formation. Further studies are needed to establish an association with much closer focus to dental prosthesis role in development of such tumors with proper assessment of the denture status in terms of stability and hygiene. More studies are also needed to examine PLAG1 and HMGA2 genes in patients with PAs with a history of trauma, for any genetic mutation/fusion.