Risk factors for recurrence of pleomorphic adenoma

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1 Risk factors for recurrence of pleomorphic adenoma Authors Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection Krzysztof Kiciński ECBFG, Bogusław Mikaszewski D, Czesław Stankiewicz A Department of Otolaryngology, Medical University of Gdansk, Head: Prof. Czesław Stankiewicz, MD, PhD Article history: Received: Accepted: Published: ABSTRACT: KEYWORDS: Pleomorphic adenoma is the most frequent benign tumor of the salivary glands. It is characterized by a tendency to recur, which is determined by the biological characteristics of the tumor as well as the mode of its treatment. Recurrence of the tumor is associated with a high risk of postoperative facial palsy, risk of subsequent recurrence after revision surgery, and an increased risk of malignant transformation. Knowledge of the recurrence risk factors could allow selection of treatments that minimize the risk. Among the factors in this study the most important are: incomplete excision, intraoperative capsule rupture, myxoid subtype, presence of the satellite nodules and tumor extensions (pseudopodia), lack of the glandular tissue margin and the experience of the surgeon. The possible factors are: the female sex, young age, location and size of the tumor, and the duration of the tumor growth. The technique of tumor enucleation of pleomorphic adenoma carries a high risk of recurrence and should be replaced by parotidectomy. In cases of recurrence the treatment is individually tailored and may include: further follow-up, limited resection of the tumor, lateral parotidectomy or extended radical parotidectomy with concurrent reconstruction of the facial nerve. The role of radiotherapy is discussed. pleomorphic adenoma, risk factors, recurrence, tumor capsule INTRODUCTION Pleomorphic adenoma, also known as benign mixed tumor, is the most frequent benign tumor of the salivary glands. The term mixed tumor was first used by Virchow in 1863, and was popularized by Minssen in 1874 [ cit. by 1]. In 1953 Willis introduced the term pleomorphic adenoma to emphasize the epithelial origin of the tumor, considering the term mixed tumor inappropriate. ORIGIN OF THE TUMOR Pleomorphic adenoma (PA) microscopically contains two components: epithelial and mesenchymal. There are two histogenetic hypotheses. According to the first one the tumor has a dual structure and it is formed simultaneously with epithelial and mesenchymal components. The second hypothesis suggests the tumor is of epithelial origin, and the mesenchymal component results from metaplasia of the stroma, caused by chemical substances secreted by the tumor epithelium. It was proved that pleomorphic adenomas derive from the cells of the glandular epithelium of the salivary glands and the myoepithelial cells [2]. The myoepithelial cells derive from totipotential stem cells explaining the morphological variety of the pleomorphic adenoma, which is characterized by a biphasic growth of epithelial or myoepithelial cells [3]. CHARACTERISTICS OF THE TUMORS Pleomorphic adenomas constitute between 53 and 85% of the benign tumors of the parotid gland. Approximately 90% of them are localized in the superficial lobe of the parotid gland, usually in its lower pole or the anterior portion. Another 5 to 10% occur in the submandibular gland and very rarely in the other salivary glands. PAs are more common in women. The age range of patients is large, from childhood to elderly, but it is diagnosed most often in the third and fifth decade of life. Usually the tumor is single and unilateral, characterized by a slow expansive growth and a greatly variable duration of the disease from 2 we- DOI: /

2 eks up to 30 years [2]. PAs are usually spherical and have smooth or lobular surface. They are cohesive and mobile. Their size varies from a few millimeters to several centimeters, and usually its size is 3-4 cm. The growth is asymptomatic. Macroscopically PAs are surrounded by a translucent capsule, sometimes thickened and mat, which can be easily separated from the tumor mass. The capsule usually surrounds the entire tumor, but it may be incomplete, focally thin, interrupted by tumor extensions or satellite nodules. Based on the amount of the stromal component, PAs are divided into three subtypes (Seifert et al. classification): cellular subtype with the stroma content of 20-30%, classic subtype with the stroma content of 30-50% and myxoid subtype with the stroma content up to 80% [4]. RECURRENCE OF PA PAs have a tendency to recur, which is related to their biological characteristics as well as the treatment method. An important role is played by the structure of the tumor capsule, which may have a focal absence of encapsulation, and through these areas the tumor forms digitate tumor extensions that can penetrate into the surrounding salivary gland tissue. Incorrect surgical procedure, i.e. enucleation of the tumor is a reason for local recurrence. Since part of the tumor is left during surgery it would be more accurate to consider this condition as residual disease than local recurrence. Recurrences are frequently multicentric, and each recurrent tumor tends to subsequently relapse. Recurrent PAs are usually multinodular. Relapses can occur in the first year after surgery or as late as after years, as illustrated in the study of Wierzbicka et al., where the average time to recurrence was 13 years [5]. The recurrence rate in the parotid gland is dependent on the surgical method: it is observed in 50% of cases after enucleation, while in only 2 to 12% of cases after parotdectomy. Recurrences of PA after parotidectomy occur with a different frequency in different reports: from 0 to 2% in Stennert et al., from 7.1 to 10% in Sikorowa, and 12.5% in Ożdziński et al. The recurrence rate of PA in the submandibular gland is about 4% and it is very rare in minor salivary glands [6]. Recurrence is associated with a high risk of the facial nerve paresis (reoperation may increase the risk of injury of the facial nerve by 70%) and lack of radical treatment at a significantly more difficult surgery. Recurrent tumors were observed in the scar tissue, loosely dispersed in the fat tissue, and in the residual tissue of the parotid deep lobe. Increased risk of tumor recurrence is observed in the myxoid subtype of PA which is characterized by a thin capsule or an incomplete capsule, and the recurrent tumors without capsule are loosely scattered in the fat tissue. Stennert et al. investigated the recurrent tumors and found that in 90% of patients they were multiple with the average number of tumors being 58. The amount of recurrent tumors was poorly estimated before reoperation by diagnostic imaging methods such as ultrasound and MRI [7]. In the study of Zbären et al., multifocal recurrence was observed in 73% of cases [8]. Based on histological studies of recurrent PA it becomes clear that the majority of relapses is multifocal and recurrent tumors are often widely dispersed in the surrounding tissues. Recurrence of PA is much more common than initially predicted, an accurate assessment of the relapse extension is difficult and imaging studies often do not determine the actual state of the disease. In addition, the tendency for multiple recurrence had been found in 30-50% of patients [9, 10]. One of the problems with recurrent PA is the increased risk of malignant transformation, which is estimated at 5-20% [11]. MALIGNANT PA PA also can undergo a malignant transformation. Such a situation is rare and is observed in 4.5% of cases. There are 3 types of malignant PA: carcinoma ex pleomorphic adenoma, a true malignant mixed tumor, and metastatic pleomorphic adenoma. The true malignant mixed tumor is observed very rarely, with both components of the tumor being malignant (carcinosarcoma), and the disease being very aggressive. Metastatic PA is a rare, histologically benign tumor. In this disease after removal of the primary tumor the distant metastases are observed, which are also associated with the local recurrence of PA. Although the histology has no features of malignancy, the clinical course of metastatic PA is associated with mortality in 20% of patients. Carcinoma ex PA is the most common form of the malignant PA. It can develop in the primary of the recurrent tumor. The malignant component has an epithelial origin. The most common types of carcinoma developing in PA are: adenocarcinoma, undifferentiated carcinoma, salivary duct carcinoma, poorly differentiated adenocarcinoma, mucoepidermoid carcinoma, and myoepithelial carcinoma. Carcinoma ex PA often metastasizes to the neck lymph nodes and to the distant organs [12]. The frequency of malignant transformation is related to the duration of disease. The risk of malignancy is approximately 1.5% over the first five years and increases to about 9% after more than 15 years. Factors that are associated with a higher probability of malignant transformation include the tumor recurrence after 40 years, male gender, recurrent tumor greater than 2 cm in diameter, and the number of relapses of over 4 [13]. Studies on the expression of the protein p53, a product of a tumor suppressor gene, and antigen of the proliferating cells PCNA showed absence of 2

3 expression of both markers in the cells without atypia, while atypical cells had increased levels of expression of both p53 and PCNA. Based on these studies it was suggested that atypical cells expressing both of these antigens are the starting point of carcinoma in PA [14]. RISK FACTORS FOR RECURRENCE OF PA Incomplete excision and intraoperative rupture of the tumor capsule The most common cause of the PA recurrence is an incomplete removal of the tumor, which is directly related to the characteristics of the tumor capsule. The capsule can be easily damaged especially when the tumor enucleation is performed instead of parotidectomy. Reduced extent of surgery and lack of accurate preoperative imaging may constitute significant risk factors for PA recurrence due to the possibility of leaving a fragment of the tumor behind [15]. McFarland noted already in 1930 that significant rate of recurrences was associated with the tumor enucleation and this relation was explained by Patey and Thackray who showed the lack of continuity in the tumor capsule with presence of gaps and tumor extensions (pseudopodia) outside the main tumor mass [16,17]. Thus, the operation near the tumor capsule associated with the risk of damage of the capsule and consequently recurrence of the tumor.[18,19] In the study by Riad et al., surgical damage to the tumor capsule was found in 14% of cases, of which 27% recurred. In that study involving 156 tumors, no recurrence was observed when capsule was preserved during surgery. However, out of 5 cases in which the spillage of the tumor during surgery took place, the recurrence was observed in 4 cases [20]. Damage to the tumor capsule and fragmentation of the tumor during surgery is the most dangerous risk factor for recurrence. Stręk et al. observed the tear of the capsule in 52% of tumors with subsequent relapse. The remaining recurrences were caused by satellite nodules or tumor extensions left behind after enucleation [21]. The following morphological features of the tumor capsule affect the risk of damage to the tumor during surgery, thus leaving behind a fragment of the tumor tissue, which is equivalent to the recurrence of the disease: Incomplete capsule and focally thin capsule: It has been shown that almost all PAs have focally very thin capsule. More than two-thirds of myxoid type adenomas and at least half of all PAs show focal defects in the capsule [22]. Stennert et al. showed loss of 4% of the tumor surface while examining all subtypes. In the myxoid subtype the losses were up to 28% of the entire circumference [15]. The incidence of capsule defects in the study of Zbären et al. was 33% [23]. Herniations of the capsule: These were much more frequent in the cellular subtype and were present in 42% of cases, while in the myxoid subtype were found in 8% of cases. The capsular herniation was observed in 26% of tumors [23]. The tumor extensions (pseudopodia): Observed in 40% of tumors. The relation of their incidence to the PA subtype had not been published. The tumor extensions can be an important risk factor for PA recurrence after enucleation of the tumor [23]. Tumor extensions were observed in 56% of the recurrent tumors and in only 8% of tumors in which there was no relapse, so their presence should be considered as a risk factor for recurrence of PA [9]. Satellite nodules: It is often difficult to distinguish the satellite nodule from tumor extensions (pseudopodia). In the study of Zbären et al., the satellite nodules were found in 13% of cases, and together with tumor extensions in 48% of cases [23]. Myxoid subtype Recurrence was observed most frequently in case of myxoid PA, which is characterized by presence of interruptions in the capsule, satellite nodules, tumor extensions and focally thin capsule [24]. It has focal absence of the capsule and frequently the tumor tissue is merging into the parotid parenchyma (70% of all cases). In the assessment of the recurrent tumors the myxoid subtype was predominant. Stennert et al., showed that 10 of 31 tumors contained only myxoid nodules, 65% of the nodules were predominantly myxoid, and in 80% their presence was found in each case [15,25]. Since almost all PAs are characterized by a high number of thin fragments of the capsule, nearly half of adenomas have a focal defect of the capsule, and one third have tumor extensions, any surgical procedure near the periphery of the tumor carries a risk of damage to the capsule and the possibility of seeding of the tumor. The high frequency of occurrence of these characteristics is an indication for parotidectomy. 3

4 The margin of unchanged glandular tissue around the tumor In the study of Raid et al., the tumor recurrence was inversely proportional to the amount of the margin of the tissue surrounding the tumor. The average size of the safety margin in patients in whom the recurrence was not observed was about 6 mm compared to 1.3 mm in the group with recurrent tumors. The safety margin was inversely correlated to the tumor size. The larger tumors had smaller margins and tumors with a diameter greater than 4 cm practically lacked any margin. The margins of 10 mm or more were observed only in tumors with a diameter of 30 mm or less. In cases where the tumor tightly adhered to the facial nerve, the recurrence was observed in 8% of cases. In cases where there was a margin of the glandular tissue, recurrence was observed only in one case, i.e. 0.9% of cases [20]. Operator experience The recurrence rate in the long-term follow-up was 2% in the study of McGurk et al., both after extracapsular excision and superficial parotidectomy. Parotid surgeries were carried out by two surgeons experienced in the parotid gland surgery. According to these authors the risk of recurrence is higher when the procedure is performed by less experienced surgeons. The authors, however, do not recommend the extracapsular excision as a routine. Superficial parotidectomy is the preferred technique for general use as it enables to avoid non-radical surgery [26]. In the paper of Guntinas- -Lichius et al., the recurrence rate was 0.6% of cases when using a microscope during surgery [25]. Duration of disease In the study of Wierzbicka et al., the mean duration of disease in patients with recurrent tumor was 66 months while in patients without recurrence 28 months. This factor was statistically significant and therefore the duration of disease was a risk factor for PA recurrence [12]. Age and sex In the study of McGregor et al., the average age of patients in whom the recurrence was observed was much lower than average age of patients without relapse in a long-term follow- -up. There are several possible explanations: PA in younger patients may be more aggressive than in older ones. Alternatively, younger patients live longer, whereby they have statistically higher risk of recurrence. These results indicate that younger patients with PA should be followed up for many years [8,27,28,29]. PA is more common in women, who also have higher recurrence rates. To achieve a better cosmetic effect in young patients a limited approach is frequently used, which may have an impact on the extend of the surgery resulting in a higher recurrence rate [10]. Zbären et al., in their study confirmed the more frequent recurrence of PA in younger patients [8]. However, in the study by Wierzbicka et al., recurrences were more frequent in the elderly patients, and gender did not increase the risk of recurrence. Riad et al. stated that neither age nor gender of the patients was significantly related to the tumor recurrence [5,20]. Location of the tumor In the study by Riad et al., the recurrence of tumors originally located in the superficial lobe occurred in 2.2% of cases, while those in the deep lobe in 3.8%, and those in the parapharyngeal space in 16.7%. Harney et al. reported that the small percentage of recurrence after resection of the tumor located in the deep lobe could be explained by a thicker capsule of these tumors compared to the tumors of the superficial lobe. They also found a different structure of the deep lobe tumors - they have a greater number of cell elements, which results in greater resistance of the tumor capsule [20,30]. The diameter of the tumor The correlation was found between the diameter of the tumor and its recurrence. The average tumor size with no recurrence was 30 mm, compared to 43 mm for the recurrent tumors (Riad et al.). However, large tumors are not always associated with recurrence and among the tumors exceeding 60 mm in diameter there was no further increase in the incidence of recurrence [20]. DISCUSSION In excision of PAs, the enucleation technique should be replaced by parotidectomy in order to reduce recurrence rate from 20-45% to less than 4%. The incidence of recurrence after superficial parotidectomy is 2-5%, and less than 0.4% after total parotidectomy [31,32,33]. In a case of the first recurrence of PA the treatment of choice is total parotidectomy with a resection of the surrounding fat tissue and preservation of the facial nerve. In case of repeated recurrences the procedure is chosen on a case by case basis, with choice of: observation, limited resection, lateral parotidectomy, or extended radical parotidectomy with reconstruction of the facial nerve [34,35]. Role of radiotherapy in the treatment of PA is still discussed [36]. Some authors suggest that 4

5 this method should be applied only in malignant tumors, as it involves the risk of inducing secondary malignancies [37]. Douglas et al. reported on their experience with the use of the neutron beam radiation and recommended the treatment in cases in which 1) the radical resection is not possible, 2) there is a significant risk of damage to the facial nerve, or 3) there have been multiple recurrences [38]. Discovery of higher expression of the progesterone receptor (PR) in the recurrent tumor cells suggests a possible future role of hormonal treatments. Currently, the presence of higher expression of PR is a prognostic factor for recurrence [39]. Complications after treatment of recurrent PA are similar to those observed after surgery of the primary PA of the parotid gland: salivary fistula, facial nerve paresis, Frey syndrome, and recurrence of the tumor. The main difference is a greater risk of injury to the facial nerve [40]. Leonetti et al. found a permanent paralysis of the facial nerve after treatment of the recurrent tumors in more than 30% of the cases [41]. The incidence of recurrence after treatment of recurrent PA ranges from 10 to 58% [8]. The risk of malignant transformation also increases (up to 15%), especially after multiple recurrences. CONCLUSION Although PA is a benign tumor, the recurrent PA is associated with a high risk of postoperative facial nerve paresis, subsequent recurrence after revision surgery, and an increased risk of malignant transformation. The possible procedures for recurrent PA are: observation, local excision, partial or total parotidectomy, revision surgery with postoperative radiotherapy, or in selected cases only radiotherapy. Many authors are consistent in their opinion that recurrences are usually locally more advanced than the clinical and radiological examinations suggest. All patients with PA before surgery should be informed about the risk of recurrence that requires further treatment. Knowledge of the biological determinants of the growth and recurrence of PA is still incomplete. It seems that the answer is hidden in the specific structure of the capsule of PA. Formation of the PA capsule is not yet clear. The classic explanation of its development is the effect of pressure on the glandular tissue by the tumor mass and by condensation and accumulation of the glandular connective tissue around the tumor. Therefore the capsule is not a product of the tumor. However this explanation seems unlikely given the considerable variation of characteristics of the capsule depending on the PA subtype. It is thought that PA capsules initially do not have holes and that they form later as a result of tumor growth. Since the theory of pseudocapsule formation cannot fully explain the peculiarities of the different histological subtypes of PA. It is reasonable to assume that the tumor itself is involved, at least partly, in the formation of the pseudocapsule. PAs composed of different cells may have different effects on the creation of the capsule leading to the differences between each of the subtypes. This is supported by the known differences in the composition of cells and proteoglycans between the outer and inner layer of the capsule [15]. The identification of factors predisposing to the recurrent disease is important because it allows to correctly choose treatment based on clinical features and tumor characteristics. Among the risk factors for PA recurrence there are some recognized in most of the studies and some that likely contribute to the risk of recurrence, but were identified in only some reports. The most important risk factors are: incomplete resection, intraoperative damage to the tumor capsule, myxoid subtype of PA, satellite nodules, tumor extensions, no margin of glandular tissue, and the experience of the surgeon. The possible risk factors are: female gender, young age, tumor location, tumor size, and duration of disease. Although PA is a well-known neoplasm, it still offers surprises and can become a difficult challenge, and further research on this tumor is still needed. REFERENCES 1. Forte F.W., Franzell L.: Tumors of the major salivary glands. Cancer, 1953; 6: Sikorowa L., Meyza J.W.: Guzy ślinianek. PZWL, Warszawa Lee P.S., Sabbath-Solitare M., Redondo T.C., Ongcapin E.H.: Molecular evidence that the stromal and epithelial cells in pleomorphic adenomas of salivary gland arise from the same origin: clonal analysis using human androgen receptor gene (humara) assay. Hum. 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7 40. Malard O., Wagner R., Joubert M., Delemazure A.S., Rio E., Durand N., Espitalier F.: Prognostic factors for secondary recurrence of pleomorphic adenoma: a 20-year, retrospective study. J. Laryngol. Otol., 2013 Sept.; 127 (9): Leonetti J.P., Marzo S.J., Petruzzelli G.J., Herr B.: Recurrent pleomorphic adenoma of the parotid gland. Otolaryngol. Head Neck Surg., 2005; 133: Word count: 3650 Tables: Figures: References: 42 Access the article online: DOI: / Full-text PDF: Corresponding author: Krzysztof Kiciński, Department of Otolaryngology University Clinical Centre, ul. Smoluchowskiego 17, Gdańsk. Tel.: ; fax: kkicinski@gumed.edu.pl, krzys.kicinski@wp.pl Copyright 2015 Polish Society of Otorhinolaryngologists Head and Neck Surgeons. Published by Index Copernicus Sp. z o.o. All rights reserved. Competing interests: The authors declare that they have no competing interests. Cite this article as: Kiciński K., Mikaszewski B., Stankiewicz C.: Risk factors for recurrence of pleomorphic adenoma. Otolaryngol Pol 2016; 70 (2): 1-7 7