The most recent World Health Organization classification of salivary gland neoplasms categorizes an MPA as a malignant epithelial neoplasm and defines it as “a histologically benign pleomorphic adenoma that inexplicably manifests local or distant metastasis” [48].

Microscopically, PA are biphasic neoplasms that can demonstrate an almost limitless number of histologic patterns. On a molecular level, PA is usually characterized by a translocation involving either PLAG1 or HMGA2, with a rearrangement identified in up to 88% of cases [7]. Current methods of histological diagnosis cannot differentiate MPA from PA (Figs. 2 and 3).

Fig. 3

Localization of pleomorphic adenoma characterised by an epithelial and myoepithelial component without atypical features with a partly chondro-myxoid mesenchymal component

Several theories have been proposed to explain the development of metastases arising from PA:

(1)

MPA is a similar but unrelated tumor to conventional PA;

(2)

MPA represents a variant of PA with specific genetics different from the typical PLAG1/HMGA2 fusions with a greater risk of malignant behaviour;

(3)

MPA originates from PA after surgical manipulation which causes vascular permeation and increases the risk of metastasis;

(4)

All PAs have an unpredictable risk of malignant transformation that only realized in a very limited number of cases.

Several authors hypothesized that previous radiation of the primary PA or previous surgical intervention might facilitate seeding and permeation of blood or lymphatic vessels by tumor cells, followed by metastatic spread. In particular, incomplete tumor excision has been strongly related with local recurrence. Nouraei et al. [49] also noted a significant association between incomplete surgical excision of the primary lesion and development of distant metastases. The evidence available to date shows that the gold standard treatment for PA is parotid surgery, specifically the performance of superficial parotidectomy [50]. Superficial parotidectomy should be preferred for PA, because capsule rupture and spillage of the tumor are the main risk factor for recurrence of the disease [51]. These complications are more frequent when extracapsular dissection (ECD) is performed. Superficial parotidectomy demonstrates greater margins due to whole gland excision when compared to ECD, therefore reducing the risk of recurrence [52]. In case of PA, meticulous resection of the tumour with adequate margins is therefore recommended, avoiding enucleation. The analysis of surgeries performed for the treatment of primary PA shows a significant heterogeneity of treatment. Although multiple parotid surgeries are found in 16 out of 42 cases (associated with RT in 47% of cases) [16,17,18,19,20, 24, 25, 28, 31, 33, 36, 39, 42, 44,45,46], MPA also developed following single surgical procedures, either partial or total parotidectomy. Moreover, both Czader et al. [53] and Fujimura et al. [54] have described cases of MPA that developed in the absence of previous treatment of salivary neoplasia. These cases are characterized by the presence of metastatic lesions (renal and bone, respectively) that occurred before the salivary lesion was evident. Both subsequently developed rapid malignant transformation at the parotid and submandibular levels respectively, with development of Carcinoma Ex-Pleomorphic Adenoma (CEPA). These cases, although exceptional, refute the hypothesis that the development of MPA is necessarily related to surgical manipulation and support the theory that there may be an inherent tendency for malignant transformation (either as MPA or CEPA) in all PAs. Mariano et al. [14] firstly reported the results of an array comparative genomic hybridization investigation conducted on the primary parotid lesion and a skin metastasis of MPA occurred 3 years after parotidectomy. Their findings showed common genomic alterations between the two lesions and indicated a clonal origin of the secondary MPA. They also detected in the parotid tumour a specific pattern of copy number alterations (3p22.2p14.3 loss and a complex pattern of chromosome 6 deletions) that could explain the ability to metastasize.

Further investigation of genetic elements or epigenetic influences is certainly advisable to identify possible determinants of malignant transformation (Fig. 4).

Fig. 4

Kaplan–Meier survival curve

According to our data, the appearance of metastatic lesions occurred in most cases several years after treatment of parotid PA. In particular, the analysed cases show that 9 patients (21,4%) developed distant disease within 5 years [14, 16, 25, 27, 34, 38,39,40, 44], while in 62% of the cases metastasis occurred after more than 10 years [9,10,11,12,13, 17, 19, 21, 22, 24,25,26, 28, 30,31,32,33, 35,36,37, 41, 43, 45, 47]. Since the performance of systemic staging is not routine in PA patients, it is not possible to define with certainty the timing of the occurrence of asymptomatic metastases.

The most frequent sites for metastasis are bone (11 patients, 26%) and lungs (11 patients, 26%) (see Table 3). The distribution of metastases does not appear to be predictable; for instance, there is no correlation with the type of surgical treatment (partial, total or multiple surgeries) or time of onset (early vs late metastases). The biological mechanisms of metastasis are still unclear; the more frequent localisation to bone and lung suggests that MPA preferentially metastasises to sites prone to blood-borne metastasis, rather than MPA having a specific tropism for these organs [19]. However, the finding of skin metastases (6 patients, 14,3% of cases) [14, 17, 19, 23, 26, 36] with constant localisation near the surgical wound or the parotid region suggests the impact of surgical manipulation on the development of such lesions. In 4 out of 5 cases [14, 23, 26, 36], metastases developed at the level of the scalp, and no skin metastases were ever reported at sites outside the head and neck district.

Our data confirmed that metastases also have a slow growth, as PA in most cases. Unfortunately, data concerning follow-up are incomplete in a significant number of patients. Among those available (24 patients), only 3 patients died due to metastasis, 7 patients were alive with disease and the others 14 were alive without disease. According to data elaborated by Nouraei et al. [49] regarding the overall survival of patients with Malignant Pleomorphic Adenoma (MPA), our findings are consistent with theirs. Nouraei et al. reported a 5-year disease-specific survival rate of 58%, which is comparable to our observed rate of 64%. However, it is important to note that our study focused exclusively on MPA of the parotid gland, whereas Nouraei et al. included MPA from various locations. Furthermore, the timing of metastatic lesion presentation significantly impacts prognosis. Patients who developed metastatic lesions within 10 years of their initial primary tumor presentation had a significantly worse prognosis compared to those whose metastases were detected more than 10 years after the initial presentation of their primary PSA.

A total of 12 patients had multiple (> 1) localizations of MPA, but follow-up status was available in only 5 cases. Among the latter, two were alive without disease, two were alive with disease, and one had died due to MPA.

Regarding the treatment of metastases, 28 patients underwent surgery and 4 patients underwent surgery followed by adjuvant radiotherapy. Only 2 patients underwent definitive radiotherapy. This data supports the role of surgery as the first treatment for MPA, if possible. The choice of treatment is obviously influenced by the site and size of the lesion, as well as the general condition of the patient. Adjuvant radiotherapy treatment has been reported in a limited number of cases and there are currently no specific treatment guidelines. To date there is still insufficient evidence to strictly recommend adjuvant radiotherapy or to propose radiotherapy as a single treatment for MPA metastases.

One of the main limitations of this study is the small number of case studies available. In the current literature, a limited number of articles describe cases of MPA of the parotid gland, and the articles available are mostly case reports, with maximum two patients for each study. Moreover, these articles often do not describe the long-term follow-up of MPA patients. Finally, there are only few studies concerning the immunohistochemical and genetic profile of MPA and the available data are not sufficient to determine and predict the behaviour and the development of the metastatic disease. The absence of these data does not allow definitive conclusions to be drawn regarding the long-term behaviour of MPA, nor does it allow the effect of different treatment protocols.

Pleomorphic adenoma is the most frequent benign tumour of the salivary glands and is one of the most frequent causes of parotid surgery [55]. Considering these premises, the search for specific histological factors related to a potential malignant transformation is desirable to identify, follow up and adequately treat high-risk patients.

For the future, more studies with a larger number of patients are needed. The analysis of the currently available data does not allow certain risk factors for metastatic development to be identified. A greater understanding of the histological, immunohistochemical and genetic characteristics of these neoplasms could provide important information for predicting the transformation of PA in MPA.

Finally, a point of discussion is the follow-up management of these patients. Considering the rarity of MPA compared to the frequency of parotid PA, what should be the most prudent course of action? According to current evidence, it is not required to perform distant PET-CT in cases of PA; moreover, long-term follow-up after successful surgery for PA does not seem essential [56]. However, considering the also very large time interval between initial parotid presentation and metastasis, patients with intraoperative tumour leakage, incomplete tumour resection or local recurrence should undergo a longer follow-up with systemic imaging.