Salivary gland malignancies

In the last twenty years, the management of salivary gland malignancies (SGMs) has evolved significantly. Intensity modulated radiation therapy, aggressive facial nerve preservation, and microsurgical free tissue flap reconstructions have become de facto standards of care [11] as results of more refined preoperative imaging, surgical techniques, and radiation protocols [6]. Nevertheless, patient outcomes have not improved accordingly [6] and the management of SGMs has remained very challenging over the decades. This is likely due to the heterogeneous biological behavior and the relative rarity of malignant parotid tumors. Here, we analyzed the outcomes of a broad cohort of patients (N=74) affected by parotid gland malignancies, whose demographic and clinical-pathologic data are comparable to other reports [6,12-14]. Although some differences in the study design, survival results are similar [1,5,7,8,12-17] and in line with the clinical common sense. Not surprisingly, indeed, patients with advanced stage or poorly differentiated tumors were more prone to develop recurrences or even die. Similarly, the presence of nodal involvement (pN+) or extracapsular spread significantly impaired both disease-specific and disease-free survival of patients. Other findings instead deserved a more detailed discussion. Despite not considered in different cancers as negative prognostic factor, the age at diagnosis was cause of poorer disease survival in our cohort, though not affecting the risk of developing recurrences. The reason likely resides in the different distribution of SGM histotypes between aged (≥55) and young (<55) patients (p<0.05).

Despite tumors of the salivary glands typically arise in the sixth and seventh decade of life [18], some have an earlier peak of onset, such as mucoepidermoid (MEC) [19] and acinic cell (AciCC) [20] carcinomas.

About 41% of our patients was younger than 55 years at the time of diagnosis, a few even in pediatric age also. Among these we detected a higher incidence of MEC (26.7% vs 6.8%) and AciCC (33.3% vs 13.6%) as expected, and interesting a lower incidence of squamous cell carcinoma (SCC, 18.2% vs 3.3%). The firsts (MEC and AciCC) have been generally linked to better prognosis above all for their low and intermediate grades, whereas the last (SCC) is otherwise renowned for its poor outcomes. This trend was confirmed also in our cohort, in which SCC had 45% 5-year DSS with respect to either 90.9% or 100% of AciCC or MEC, as worse as 37.5% DFS after 5 years if compared to 88.9% and 100% of AciCC and MEC, respectively. Nonetheless, our follow up period is not particularly extended: as some tumors have an indolent behavior, it is possible that statistical results of studies with a 5-year follow up would be much different if the follow up has been extended to 10 years [21,22]. Adenoid cystic carcinoma (ACC), in particular, can express its lethality in a 10-15 year period [23,24]. However, the cancer hystotipe distribution we detect among our patients is concordant with that of other series [6,12-15,21,25].

Furthermore, in aged patients we found a higher incidence of tumor involving the deep lobe of the parotid gland (52.3% vs 26.7%), though the data not achieves the significant threshold (p=0.051). As already reported, the deep lobe is generally affected by malignant tumors, whereas those involving the sole superficial lobe are more frequently of benign behavior [26]. To corroborate further this finding, no patient affected by tumors localized only in the superficial lobe died in our cohort for the disease, but the disease specific survival was 52% only for those with deep lobe involvement.

Knowledge of clinical and histopathologic prognostic factors is worldwide recognized as critical to making appropriate decisions regarding therapeutic options [7,12,27]. Interestingly, none of the analyzed variable affected the locoregional control at 5-year, which remained stable at about 80%. Despite difficult to argue about, this finding could lay for a good multidisciplinary management of salivary gland malignancies.

Thus, the main pattern of failure we detect still resides in distant metastasis, which are up to now an unavoidable complication of some clinical pictures, such as high grade tumor or positive nodal involvement.

To complicate matters further, concerns are raised on the current approach to grading of SGMs, which has been subject to many deficiencies and challenges. As states by Koul et al., “the true picture is of gradation from one category to another, with a particular direction of differentiation” [7]. Determining tumor grade is difficult partly because the non-availability of consensus about the histopathological criteria for grading systems and the unpredictable long-term behavior of some neoplasms [15]. According to Sheethala, carcinoma ex pleomorphic adenoma should no longer be considered a specific diagnosis, but rather a category in which the carcinoma should be typed, graded and quantitated to impact more prognostically and therapeutically relevant data [28]. The two tumor types for which specific grading systems are evolved are ACC and MEC. ACC is graded based on growth pattern with solid growth giving a poorer prognosis. Rarely, these tumors will undergo high-grade transformation, gaining a much higher predilection for lymph node metastases than a conventional ACC. In MEC, standardized grading systems are more reproducible than generic grade assignment, but in their current form they are cumbersome and time consuming. The outcome in the intermediate grade category is heavily dependent on the grading system used and is thus the most controversial with regards to management and prognosis [28].

Another controversial topic is the neck management in malignant tumours of the parotid gland.

Neck dissection and adjuvant therapy in N+ patients presents a general consensus, while the management of cN0 has more treatment options. The main problem is the possible presence of occult metastases. The literature shows a variable percentage of occult metastases ranging from 12 to 49% [29]. This variability is related to the huge number of histologic types.

Prognostic factors of occult metastases in cN0 malignant tumours of the parotid are: T3-T4, high-grade and advanced age. In a recent review, three approaches to the neck in cN0 patients have been proposed [29]:

1) in low-risk patients, “wait and see” or prophylactic neck dissection;

2) if risk factors for lymph node metastases are discovered only at definitive histology, elective irradiation of the neck;

3) in high-risk patients, elective neck dissection II-IV or Ib-IV; elective irradiation of the neck (especially if adjuvant radiotherapy for the primary tumour has already been planned); super-selective (level I-II) or selective (I-III) and neck dissection with frozen sections and comprehensive neck dissection in presence of occult nodal disease.

Thus, this paper further emphasizes the need to research in malignant tumours of the parotid gland by high-number series randomized-controlled and prospective trials (possibly by creating clusters of tumors with similar but not identical features) in order to improve the treatment management and survival of SGM patients.

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