The pleomorphic adenoma (PA), or benign mixed tumor, is the most common salivary gland neoplasm, accounting for 60-65% of all major and minor salivary gland tumors (1). It constitutes 53%-77% of parotid tumors, 44%-68% of submandibular tumors, and 38%-43% of minor salivary gland tumors (2). It occurs frequently in females, with the female-male ratio ranging from 1.9:1 (3) to 3.2:1 (4) and with a peak incidence between the 5th and the 7th decades of life (3, 4).
The terms pleomorphic and mixed are used to describe the characteristic diverse microscopic pattern seen in this tumor, which is composed of a mixture of glandular epithelium, myoepithelial cells and connective tissue elements (2). The aetiology of PA is unknown, however clonal chromosome abnormalities with aberrations involving 8q12 and 12q15 have been associated with this neoplasm (5).
The palate followed by the upper lip appears to be the most affected intraoral site of the minor salivary glands PA (2-8). This tumor presents as an asymptomatic firm mass with a long period of slow growth rate, whereas secondary to trauma the clinical features may also include ulceration, pain or bleeding (9). The aim of this article is to report a case of upper lip pleomorphic adenoma that is of particular interest to dental clinician due to its atypical clinical presentation by resembling to inflammatory odontogenic lesion.
A 39 year old Caucasian female was referred to our private clinic for evaluation of a swelling on the right side of her upper lip . The medical history was unremarkable, as there was no reference of any other disease, no known allergies, no history of smoking and she was a social drinker. According to the dental history the patient suffered a trauma on the maxillary right incisor eight years ago, and endodontic therapy was the treatment of choice. The patient also reported the presence of a palpable, asymptomatic nodule in the above region for the past three years. Furthermore, approximately one and a half months ago the patient started feeling a subtle pain in the upper lip followed by a swelling for the past week. On intraoral clinical examination, an obliterated mucolabial fold was observed in the region of the right central and lateral maxillary incisors corresponding to the aforementioned upper lip swelling (figure 1). Head and neck abnormalities were not noted on clinical evaluation. Radiographic examination revealed the root canal therapy of the right maxillary central incisor, whereas a radiolucent periapical lesion was also apparent (figure 2). Based on the history, the clinical and radiographic features, the provisional diagnosis included lesions of odontogenic inflammatory aetiology, such as the periapical granuloma or periapical cyst. Thus, amoxicillin 500mg/6h was prescribed for a week, resulting in a moderate recession, while the pain had subsided.
On re-examination after one week, a persisting mobile, well circumscribed tumor-like lesion measuring 1cm x 0.7cm was seen in the mucolabial fold. Apicoectomy and retrograde filling was decided over repeating the root canal therapy. Under local anaesthesia (xylocaine 2% with 1:100000 epinephrine) access to the apex of the tooth was achieved through a triangular flap consisting of a horizontal intrasulcular incision of the teeth 12,11and 21 and a vertical releasing incision distal to the tooth 12.A full thickness mucoperiosteal flap was elevated and a nodular, firm soft tissue mass was revealed which was not related to the periapical lesion. The mass was located at the depth of the mucolabial fold and was extended into the orbicularis oris muscle (figure 3). Excisional biopsy of the soft tissue mass was performed followed by enucleation with local curettage of the intraosseous periapical lesion. Haemostasis was achieved, the apical third of the root was resected and the retrograde filling was completed using Super EBA. The area was sutured with 3:0 silk and the post-operative course and healing was uneventful. The histopathologic examination of the soft tissue tumor revealed an encapsulated lesion that showed cellular areas with epithelial cells arranged in cord and duct-like structures filled with eosinophilic material (figure 4). The intercellular matrix demonstrated fibrous, hyaline and myxoid areas (figure 4). The histopathological diagnosis was pleomorphic adenoma. The histopathology of the intraosseous periapical lesion demonstrated fibrous connective with intense inflammatory cell infiltration consistent with periapical granuloma. There was no evidence of recurrence after three years follow up.
In the case presented here, lesions of two different aetiologies, located in the same anatomic region resulting clinically in lip swelling. Clinical differential diagnosis of upper lip swellings includes a wide range of neoplastic or inflammatory pathological entities: benign and malignant salivary gland tumors, oral cysts (mucocele, salivary duct cyst, nasolabial), minor salivary gland sialolith, mesenchymal tumors, such as hemangioma, neurofibroma, neurilemoma or infection secondary to foreign body’s reaction. Several diseases such as orofacial granulomatosis, Melkersson-Rosenthal syndrome, tuberculosis and actinomycosis include lip swelling in their range of clinical manifestations (2, 10-12) (Table 1).
Cited in Neville 2002, p.798
The clinical features contribute to the differentiation between benign and malignant lesions. Several studies have shown that the vast majority of upper lip tumors are benign (7, 13-15), while malignant tumors tend to predominate in the lower lip (13-15). Benign lesions usually present as asymptomatic slow-growing (average course 3-6 years), well-defined, smooth, and uniform nodular tumors showing a normal overlying surface color, and lack of adherence to superficial or deep tissue layers. Malignant lesions, on the other hand, may be painful, fast-growing (average course of less than one year), and may exhibit bleeding, ulceration, infection, adherence to deeper or superficial layers, and even lymph node involvement (10).
Upper lip stands second in predilection for location of intraoral PA with a ratio of 6:1; (3, 13, 16). In the study of Kroll and Hicks (16), 14.5% of the 445 cases of minor salivary glands PA were located in the upper and only 2.5% in the lower lip. The higher relative frequency can be attributed to the more complex embryologic development of the upper lip compared to the lower lip. The fusion of the three embryonic processes that form the upper lip comes with a higher possibility of entrapment of embryonic cell nests. This is further supported by the fact that the upper lip PAs are commonly located on either side of the midline corresponding to the fusion lines (11, 17-19). Intraosseous glandular neoplasms most commonly mucoepidermoid carcinoma have been reported in the literature (20, 21), whereas the incidence of the central PA is rare (20). Salivary tissue entrapment during the embryonic development, or metaplasia of the odontogenic cysts epithelial lining have been suggested to be involved in the pathogenesis of these neoplasms (20). The central salivary gland tumors may mimic clinically and radiographically odontogenic inflammatory lesions, because of their close relationship with teeth, resulting in an unsuspected diagnosis. There are certain criteria to evaluate in order to render a diagnosis of a salivary gland tumor of central origin. First, there should not be any preexisting or concurrent primary tumor of salivary glands. Second, the cortical bone above the lesion should preserve its integrity, and last, a positive histological diagnosis of salivary gland neoplasm is needed (22). The synchronous development of PA and odontogenic cyst within the same region has also been reported (21). In our case, the PA potentially arising from the minor lip salivary glands extended to the mucolabial fold; the tumor was not associated with the central periapical lesion, since the cortical maxillary bone was intact based on the intraoperative findings. The symptoms of the odontogenic periapical inflammation were the reason for the patient’s visit to our clinic leading to the diagnosis and management of the intraoral PA.
PA may infrequently undergo malignant transformation with an incidence between 1.9% and 23.3% of the cases (23-31). Local clinical manifestations of malignancy, regional or distant metastasis, in addition to histopathological features, such as invasion and cellular atypia, usually lead to the diagnosis of malignant transformation. The three common subtypes of malignant PA are: carcinoma ex pleomorphic adenoma (representing 12% of malignant neoplasms), carcinosarcoma or true malignant mixed tumor and metastasizing mixed tumor. The carcinoma ex pleomorphic adenoma is the most common, characterized by malignant transformation of the epithelial element of an initially benign PA. In such cases, the patient’s medical history may usually reveal the long duration of the tumor that presented rapid growth accompanied by pain and/ or ulceration. However, some lesions may manifest short duration without recent sudden growth and even without pain, leading to a malignant PA indistinguishable from a benign lesion. This highlights the importance of the awareness and high suspicion essential for the treatment of PA (2).
Malignant transformation may be associated with incomplete surgical removal of a benign PA (10), and the most important risk factor appears to be the elapsed period without the necessary treatment. The longer the PA remains untreated, greater is the risks (2, 32). According to the literature, when treatment has been delayed for more than 15 years, malignant transformation applies for 9.4% of cases, compared to 1.6% of tumors remaining untreated for less than 5 years. The latter underlines the importance for early and correct diagnosis with an early and definite treatment of PA (33).
Surgical removal is the treatment of choice for minor salivary gland neoplasms. The lesion should be removed together with a margin of the surrounding normal tissue, of at least 1 to 2 cm in the case of a malignant neoplasm. In the earlier years benign mixed tumors were enucleated, but the simple tumor enucleation may be associated with a higher recurrence rate. Aggregates of tumor cells are often left behind and especially when this is combined with an incomplete encapsulation of the tumor (34). Minor salivary gland tumors have a high recurrence rate 5-30% when surgical removal is inadequate, while the percentage rises to 65% in case of malignant salivary neoplasms. This capacity to relapse is related to the histopathological characteristics of the tumor, and particularly to the initial treatment provided (10). In our case the encapsulated lesion was totally removed and there are no signs of recurrences three years after the surgery. The follow up of patients is essential and should be long due to the possibility of late recurrence.
The clinical diagnosis of the intraoral salivary gland neoplasms located near the teeth-bearing oral mucosa sometimes may be challenging, because of the potential overlapping clinical signs and radiographic features between inflammatory jaw lesions and oral tumors. Despite the rare incidence of two different pathologic entities within the same anatomic region, vigilance on behalf of the dental practitioner is always required concerning the lip or perioral swellings.