1

Introduction

Pleomorphic adenoma (PA) is the most common form of salivary gland neoplasm, representing 80% of all salivary tumours [ ], of which 60% are benign [ ]. PA is known for its tendency to recur and the possibility of transformation into carcinoma ex pleomorphic adenoma (CXPA) [ ]. The recurrence of PA has been attributed to unencapsulated nature of the lesion and rupture of the tumour capsule during surgery that makes surgical removal challenging [ ]. CXPA arises from a primary or recurrent benign pleomorphic adenoma [ ]. It is defined as a tumour with evidence of malignancy, characterized by anaplasia and abnormal mitotic activities [ ]. The pathogenesis of CXPA is controversial. Two hypotheses are mentioned in the literature: a) these tumours are malignant from the onset, and b) a carcinomatous transformation of a mixed tumour occurs [ ].

CXPA is the most common of the three subcategories of malignant mixed tumours of the salivary glands [ ]. From the available litterature, CXPA is considered to be an aggressive malignant carcinoma with commonly occurring regional metastases and a high mortality rate [ ]. The neoplasm generally affects the major salivary glands, especially the parotid and submandibular glands [ , , ]. Patients with CXPA often have a prolonged history of untreated or recurrent benign pleomorphic adenoma [ , ]. Diagnosis of CXPA is often challenging for clinicians, surgeons, and pathologists [ ]; misdiagnosis is common because the residual PA component may be small and therefore missed during histological analysis. In addition, various other carcinoma subtypes may also be present [ , ].

Statistics regarding the prevalence of CXPA vary between studies [ ]. It reportedly represents approximately 3–5% of all salivary neoplasms and 12% of all salivary glands malignancies [ , , , ]. CXPA shows a predilection for females and is commonly seen in the sixth or seventh decade of life [ , ]. CXPA includes the same genetic abnormality as the PA precursor; the accumulation of additional aberrations is believed to lead to the malignant transformation. The main histopathological finding in CXPA is the co-existence of the benign characteristics of PA and malignant changes in the epithelial components of the tumour [ , ]. The relative proportions of adenomatous and carcinomatous components determine the macroscopic features of the neoplasm [ ]. Malignant transformation of PA often presents as a sudden increase in size accompanied by local signs such as ulceration, spontaneous bleeding, and superficial and deep tissue invasion [ , ]. As with most other salivary gland malignancies, the main treatment is ablative surgery, which may or may not include radiotherapy [ , ]. CXPA has a poor prognosis; however, accurate diagnosis and aggressive surgical management may increase survival rates [ ].

Despite considerable research on CXPA and the associated prognostic factors—including tumour size, grade, proportion of carcinomatous component, extent of invasion, and proliferation index—this neoplasm is still poorly understood [ ]. There is a need to better understand the behaviour of CXPA, and to assess the prognostic significance of the carcinomatous component for accurate diagnosis and treatment planning. Few cases of CXPA in the submandibular gland with a poor prognosis have been reported in the literature [ ]; most published cases focus on the parotid gland. In this report, we presented an unusual case of CXPA in the submandibular gland that clinically mimicked a benign lesion. We discussed the clinical and histopathological diagnosis, patient survival rate, and factors that may affect management outcomes.

2

Case presentation

A 69-year-old male was admitted to the Department of Oral and Maxillofacial Surgery and the Second Affiliated Hospital of Stomatology, Jiamusi University, with enlargement of a mass in his submandibular gland that had persisted for many years without pain. Clinical examination revealed deformation of the right submandibular gland region, with a cervical mass extension measuring 12 × 10 cm ( Fig. 1 A). The mass was moderately firm in consistency, was not fixed to the neighbouring tissues, and did not elicit pain during palpation. The superjacent skin was normal, cervical lymphadenopathy was not palpable, and inspection of the oral cavity was normal. Preoperative computed tomography showed a homogeneously enhancing mass in the right submandibular gland ( Fig. 1 B) with no evidence of lymph node involvement. Based on these clinical and radiological findings, the mass was diagnosed as a benign salivary gland neoplasm of the submandibular gland—most likely a pleomorphic adenoma. The chosen treatment plan was a submandibulectomy under general anaesthesia.

A: Preoperative patient presentation; B: Axial computed tomography scan showing a homogeneously enhancing mass in the right submandibular gland; C: Excised submandibular mass.

Macroscopic examination of the excised tissue revealed an encapsulated, well circumscribed mass with the multiple nodules, measuring 10.8 × 10 × 9 cm ( Fig. 1 C). The surface of the capsule was intact with a gray-brown colour and no apparent calcification. The specimen was fixed in 10% buffered formalin and embedded in paraffin. Histopathological examination of the tissue revealed a CXPA consisting of myxoid, chondroid, and fibrous stromata, as well as duct-like structures and cell-rich mesenchymal tissues ( Fig. 2 ). The mass was well encapsulated, without rupture of the fibrous capsule, and was classified as a T4N0M0 carcinoma. There was no evidence of recurrence at the time of writing this report, six years post surgery.

A: Histopathological image of the excised carcinoma ex pleomorphic adenoma from the right submandibular gland (magnification: 10 × ); B: Histopathological image of the excised submandibular gland mass (magnification: 40 × ).

3

Discussion

CXPA represents 5–15% range instead of 12% for all salivary gland malignancies. Misdiagnosis is common due to the possibilities of a small residual PA component and the presence of various carcinoma subtypes. Many studies consider CXPA as a highly malignant carcinoma with poor prognosis. Frequently, the lesion leading to metastasis and disease-related death. Previous studies identified several clinicopathological factors with an unfavourable correlation with CXPA prognosis, including advanced stage, lymph node involvement, extent of invasion, tumour type, and grade [ ]. In the aforementioned study [ ] Zhao et al. reported that none of their patients were still alive 10 years after initial treatment. A review by Gnepp et al. [ ] found that 5-year survival ranged 25–65%. In the case presented in this report, no complications were noted during a 6-year post-surgery follow-up. Study have investigated the prognostic factors affecting the clinical outcomes of CXPA in the major salivary glands [ ]. Local regional recurrence and distant metastases were the main reasons for treatment failure. As expected, patients with a high T stage, lymph node involvement, or those older than 55 years had worse overall survival and unfavourable clinical outcomes. However, some argue that older patients are often associated with more advanced disease stages and are also more likely to die of non-tumour causes [ ]. Interestingly, our case of a 69-year-old with a T stage 4 CXPA did not experience any unfavourable clinical outcomes. The fact that CXPA is a rare condition may explain the low number of cases reported in the literature; more studies are required to further investigate CXPA. Additionally, CXPA can be divided into 3 subtypes—non-invasive, minimally invasive, and invasive—according to the presence and extent of invasion of the carcinomatous component outside the fibrous capsule [ , , , ]. The unusual case in this study was a non-invasive CXPA because the histopathological examination revealed that the surface of the fibrous capsule was intact with no signs of invasion by the malignant component. The non-invasive nature of this CXPA may have contributed to favourable treatment outcome in this case report.

Although non-invasive CXPA marks the beginning of the malignant transformation, it tends to exhibit the benign behaviour of PA [ ]. Our observation is consistent with a study by Zhao et al. [ ] in which none of their 12 patients with minimally invasive or non-invasive CXPA experienced recurrences, metastases, or death. Increased extent of invasion was found to positively correlate with higher CXPA recurrence and worse survival rates.

The malignant component of CXPA is most frequently a poorly differentiated adenocarcinoma or undifferentiated carcinoma [ , ]. However, other malignancies such as mucoepidermoid, squamous cell, adenosquamous cell, adenoid cystic, and epithelial myoepithelial carcinoma have also been reported [ ]. Katabi et al. [ ] reported that the presence of the myoepithelial carcinoma subtype appeared to increase the risk of recurrence in CXPA. Malignant changes in PA have been associated with a longer duration of the tumour, as well as for the tumour recurrence, radiation therapy, advanced age, large tumour size, and location of the tumour in a major salivary gland [ , , , ]. The risk of malignancy transformation increases by 1.5% after 5 years of PA duration and by 10% after 15 years [ , , ]. Stodulski et al. [ ] estimated that the malignant transformation of PA occurs in 5–25% of untreated patients, usually after 15–20 years, and warning symptoms were present in most cases. In the present report, only a long duration of tumour persistence, large tumour size, and location of the lesion in a major salivary gland were found; the patient did not have a history of tumour recurrence or treatment with radiotherapy. Andreasen et al. [ ] and Valstar et al. [ ] found that the rate of CXPA in recurrent salivary gland PA was 3.2%. Valstar et al. [ ] defined 3 risk factors for PA recurrence transformation: incomplete marginal surgical resection, patient age, and location of the lesion.

CXPA symptoms are quite similar to those presented by a benign PA; therefore, it is important that clinicians and surgeons maintain a high level of clinical suspicion [ ]. Most patients with CXPA present with an uneventful mass for many years before sudden growth, facial paralysis, or local pain occur [ ]. The most familiar clinical manifestation of submandibular gland CXPA is a mass with hard or firm consistency [ , ]. Sometimes the mass can be as asymptomatic as PA, especially if it is non-invasive [ , ]. In the present case, there were no features that indicated the presence of a malignant PA according to the patient’s clinical and radiographic history available to the surgeon. Many studies have confirmed that the typical clinical characteristics of CXPA are a long history of PA (average 10–15 years), advanced age, location in a major salivary gland, and a sudden period of rapid growth (average 3–6 months). Only 30% of patients present symptoms, including pain, facial nerve palsy, enlarged lymph nodes, skin fixation, skin ulceration, and dysphagia [ , , , ]. Local recurrence is more common than metastasis; the most common site of metastasis is the neck, followed by the lungs [ , ].

Diagnosing CXPA may be difficult on the basis of clinical data alone [ ]. Therefore, histopathological examination remains the gold standard for the definitive diagnosis of CXPA, which is based on the co-occurrence of epithelial malignancy with histologically benign PA [ , , ]. Fine needle aspiration cytology, computed tomography, and magnetic resonance imaging (MRI) may also be appropriate diagnostic modalities for confirming CXPA diagnosis prior to surgery [ ]. Asaumi et al. [ ] reported that dynamic MRI was useful in distinguishing malignant tumours, as well as detecting the extent of invasion. The treatment for CXPA often involves a surgical procedure with or without chemotherapy or radiotherapy, depending on the case [ ]. In most salivary gland malignancies, postoperative radiation therapy was used as an adjuvant therapy in patients with adverse risk factors [ , , ]. However, based on a low incidence of CXPA, there are few studies that have evaluated the role of radiotherapy specifically for CXPA. In the present case report, a submandibulectomy without any adjuvant therapy was performed, and no recurrence was observed 6 years post-surgery. In their retrospective analysis of 63 CXPA patients, Chen et al. [ ] observed that the use of post-operative radiotherapy significantly improved local control but was not associated with higher survival rate. Surgical approaches must be individually tailored on the basis of the tumour location, involvement of adjacent structures, patient age, and histological subtype of CXPA.

4

Conclusion

CXPA is a malignant lesion with a variety of clinical presentations. Clinicians, surgeons, and pathologists need to better understand CXPA clinically and pathologically to avoid misdiagnosis and subsequent choice of an inappropriate treatment plan. Ablative surgery is currently the primary treatment for CXPA and must be individualized according to clinical features (e.g., tumour size, tumour location, patient age) and the subtype classification of the tumour. Post-operative monitoring is of utmost necessity to detect relapse at an early stage.