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Clinical behavior of recurrent pleomorphic adenoma in the palate: a systematic review

ABSTRACT

Purpose:

This systematic review analyzed the clinical behavior and odds of malignancy of the palatal recurrent pleomorphic adenomas.

Methods:

Systematic review of patients with recurrent pleomorphic adenoma arising in the palate. Database search: MEDLINE, Scopus, Web of Science, Cochrane, EMBASE, Virtual Health Library, Google Scholar, and OpenGrey. A binomial logistic regression was performed to assess the odds of detecting recurrence five, 10 and 20 years after the treatment of primary tumor.

Results:

Thirteen studies (n = 18 patients) out of 336 were included. The recurrent pleomorphic adenoma in palate was more common in females (61.6%), average age was 49 years old (range 9–73 years old). Four patients progressed to malignant transformation. The odds ratio (OR) of detecting a recurrence at 10 (OR = 5.57; 95% confidence interval – 95%CI 1.13–27.52), and 20 years (OR = 18.78; 95%CI 3.18–110.84) after treatment of primary pleomorphic adenoma was significantly higher than at one-year follow-up.

Conclusions:

The recurrence of pleomorphic adenoma in palate remains a rare event of late occurrence. It mainly affects middle-aged female and carries a risk of malignant transformation. Although uncommon, patients with palatal pleomorphic adenoma should be warned about the possibility of recurrence or malignant transformation of tumor at advanced ages.

Key words
Neoplasms; Adenoma, Pleomorphic; Salivary Glands; Recurrence

Introduction

Pleomorphic adenoma is the most common type of benign salivary gland tumor and may develop in the major and in the minor salivary glands11 Almeslet AS. Pleomorphic Adenoma: A Systematic Review. Int J Clin Pediatr Dent. 2020;13(3):284–7. https://doi.org/10.5005/jp-journals-10005-1776
https://doi.org/10.5005/jp-journals-1000...
,22 Bruzinga FFB, Fernandes FCF, Dias FR, Lima MG, de Souza PEA, de Aguiar MCF, Grossmann S de MC. Clinical and demographic features of minor salivary gland tumors: A collaborative study of 480 cases. Oral Dis. 2023;29(3):1028–38. https://doi.org/10.1111/odi.14119
https://doi.org/10.1111/odi.14119...
. Approximately more than 30% of the pleomorphic adenomas arise in the minor salivary glands, and half of these cases occur in the palate22 Bruzinga FFB, Fernandes FCF, Dias FR, Lima MG, de Souza PEA, de Aguiar MCF, Grossmann S de MC. Clinical and demographic features of minor salivary gland tumors: A collaborative study of 480 cases. Oral Dis. 2023;29(3):1028–38. https://doi.org/10.1111/odi.14119
https://doi.org/10.1111/odi.14119...
,33 Wu YC, Wang YP, Cheng SJ, Chen HM, Sun A, Chang JYF. Clinicopathological study of 74 palatal pleomorphic adenomas. J Formos Med Assoc. 2016;115(1):25–30. https://doi.org/10.1016/j.jfma.2015.09.008
https://doi.org/10.1016/j.jfma.2015.09.0...
. Clinically, pleomorphic adenoma in palate has good prognosis, and it typically appears as a slow growing and asymptomatic solitary nodule, completely or partially surrounded by capsule, that may cause compressive bone resorption11 Almeslet AS. Pleomorphic Adenoma: A Systematic Review. Int J Clin Pediatr Dent. 2020;13(3):284–7. https://doi.org/10.5005/jp-journals-10005-1776
https://doi.org/10.5005/jp-journals-1000...
. Despite of most palatal pleomorphic adenomas are partially or nonencapsulated33 Wu YC, Wang YP, Cheng SJ, Chen HM, Sun A, Chang JYF. Clinicopathological study of 74 palatal pleomorphic adenomas. J Formos Med Assoc. 2016;115(1):25–30. https://doi.org/10.1016/j.jfma.2015.09.008
https://doi.org/10.1016/j.jfma.2015.09.0...

4 Ural A, Livaoǧlu M, Bekta D, Bahadir O, Hesapçioǧlu A, Imamoǧlu M, Işik AU. Approach to benign tumors of the palate: analysis of 28 cases. Ear Nose Throat J. 2011;90(8):382–5. https://doi.org/10.1177/014556131109000813
https://doi.org/10.1177/0145561311090008...

5 Vicente O, Marqués N, Aytés L, Escoda C. Minor salivary gland tumors: A clinicopathological study of 18 cases. Med Oral Patol Oral Cir Bucal [Internet]. 2008 [cited 2023 May 2];13(9):E582–8. Available from: http://www.medicinaoral.com/pubmed/medoralv13_i9_pE582.pdf
http://www.medicinaoral.com/pubmed/medor...
-66 Alsufyani NA, Altowaijri AA, Alshehri BM, Alsadhan MS. Systematic Review of Clinical and Radiographic Signs of Pediatric Pleomorphic Adenoma of Minor Salivary Glands. J Contemp Dent Pract [Internet]. 2021 [cited 2023 May 2];22(9):1063–8. Available from: https://pubmed.ncbi.nlm.nih.gov/35000954/
https://pubmed.ncbi.nlm.nih.gov/35000954...
, its recurrence after surgical treatment varies from 2% at five years to 7% at 20 years of follow-up time77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
.

Efforts to understand the factors involved in the recurrence of pleomorphic adenoma have been the focus of diverse studies and systematic reviews88 Rooker SA, Van Abel KM, Yin LX, Nagelschneider AA, Price DL, Olsen KD, Janus JR, Kasperbauer JL, Moore EJ. Risk factors for subsequent recurrence after surgical treatment of recurrent pleomorphic adenoma of the parotid gland. Head Neck. 2021;43(4):1088–96. https://doi.org/10.1002/hed.26570
https://doi.org/10.1002/hed.26570...

9 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
-1010 Riad MA, Abdel-Rahman H, Ezzat WF, Adly A, Dessouky O, Shehata M. Variables related to recurrence of pleomorphic adenomas: outcome of parotid surgery in 182 cases. Laryngoscope. 2011;121(7):1467–72. https://doi.org/10.1002/lary.21830
https://doi.org/10.1002/lary.21830...
. Some features such as gender, age of the patient at diagnosis, duration of the tumor, incomplete surgical resection, deficient encapsulation, and previous radiotherapy have been suggested as risk factors for recurrent pleomorphic adenoma (RPA)44 Ural A, Livaoǧlu M, Bekta D, Bahadir O, Hesapçioǧlu A, Imamoǧlu M, Işik AU. Approach to benign tumors of the palate: analysis of 28 cases. Ear Nose Throat J. 2011;90(8):382–5. https://doi.org/10.1177/014556131109000813
https://doi.org/10.1177/0145561311090008...

5 Vicente O, Marqués N, Aytés L, Escoda C. Minor salivary gland tumors: A clinicopathological study of 18 cases. Med Oral Patol Oral Cir Bucal [Internet]. 2008 [cited 2023 May 2];13(9):E582–8. Available from: http://www.medicinaoral.com/pubmed/medoralv13_i9_pE582.pdf
http://www.medicinaoral.com/pubmed/medor...
-66 Alsufyani NA, Altowaijri AA, Alshehri BM, Alsadhan MS. Systematic Review of Clinical and Radiographic Signs of Pediatric Pleomorphic Adenoma of Minor Salivary Glands. J Contemp Dent Pract [Internet]. 2021 [cited 2023 May 2];22(9):1063–8. Available from: https://pubmed.ncbi.nlm.nih.gov/35000954/
https://pubmed.ncbi.nlm.nih.gov/35000954...
. However, due to the limited number of reports of RPA in minor salivary glands, the studies often include tumors affecting major and minor salivary glands99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
,1111 Dimitrijevic MV, Boricic IV, Tomanović NR, Dimitrijevic AM, Bjelogrlić GM, Krstić AM, Stojkovic GM, Rajovic NZ, Djordjevic IPM, Djurkovic PM. Clinicopathological Analysis of 907 Major and Minor Salivary Gland Tumors. J Craniofac Surg. 2022;33(5):E507–9. https://doi.org/10.1097/scs.0000000000008482
https://doi.org/10.1097/scs.000000000000...
.

Similarly, the malignant transformation of oral pleomorphic adenoma occurs in less than 5% of cases and is associated to multiple recurrences and longer time of development of the lesion1212 Valstar MH, Mast H, ten Hove I, Moonen LR, Balm AJM, Smeele LE, Koljenović S, Dinjens WNM, van Velthuysen MLF. Malignant transformation of salivary gland pleomorphic adenoma: proof of principle. J Pathol Clin Res. 2021;7(5):432–7. https://doi.org/10.1002/cjp2.216
https://doi.org/10.1002/cjp2.216...

13 Andreasen S, Therkildsen MH, Bjørndal K, Homøe P. Pleomorphic adenoma of the parotid gland 1985–2010: A Danish nationwide study of incidence, recurrence rate, and malignant transformation. Head Neck. 2016;38(Suppl. 1):E1364–9. https://doi.org/10.1002/hed.24228
https://doi.org/10.1002/hed.24228...
-1414 Choi SY, Choi J, Hwang I, Cho J, Ko YH, Jeong HS. Comparative Longitudinal Analysis of Malignant Transformation in Pleomorphic Adenoma and Recurrent Pleomorphic Adenoma. J Clin Med. 2022;11(7):1808. https://doi.org/10.3390/jcm11071808
https://doi.org/10.3390/jcm11071808...
. Nevertheless, most factors associated with recurrence and/or malignancy of pleomorphic adenoma of the mouth is based in studies involving mainly the parotid gland, the most frequently affected site by this tumor11 Almeslet AS. Pleomorphic Adenoma: A Systematic Review. Int J Clin Pediatr Dent. 2020;13(3):284–7. https://doi.org/10.5005/jp-journals-10005-1776
https://doi.org/10.5005/jp-journals-1000...
,99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
,1414 Choi SY, Choi J, Hwang I, Cho J, Ko YH, Jeong HS. Comparative Longitudinal Analysis of Malignant Transformation in Pleomorphic Adenoma and Recurrent Pleomorphic Adenoma. J Clin Med. 2022;11(7):1808. https://doi.org/10.3390/jcm11071808
https://doi.org/10.3390/jcm11071808...

15 Lopes MA, Kowalski LP, Santos GDC, De Almeida OP. A clinicopathologic study of 196 intraoral minor salivary gland tumours. J Oral Pathol Med. 1999;28(6):264–7. https://doi.org/10.1111/j.1600-0714.1999.tb02036.x
https://doi.org/10.1111/j.1600-0714.1999...
-1616 EI-Naggar AK, Chan JKC, Grandis JR, Takata TSPJ. WHO Classification of Head and Neck Tumours. In: Grandis A (ed.). WHO classification of Head and neck Tumors 2017. IARC; 2017. p. 159–202. . Studies evaluating the clinical behavior of RPA arising in minor salivary glands are scarce99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
,1717 Alzumaili B, Xu B, Saliba M, Abuhashem A, Ganly I, Ghossein R, Katabi N. Clinicopathologic characteristics and prognostic factors of primary and recurrent pleomorphic adenoma a single institution retrospective study of 705 cases. Am J Surg Pathol. 2022;46(6):854–62. https://doi.org/10.1097/pas.0000000000001837
https://doi.org/10.1097/pas.000000000000...
,1818 Key S, Chia C, Hasan Z, Sundaresan P, Dwivedi RC, Riffat F. Systematic review of prognostic factors in carcinoma ex pleomorphic adenoma. Oral Oncol. 2022;133:106052. https://doi.org/10.1016/j.oraloncology.2022.106052
https://doi.org/10.1016/j.oraloncology.2...
.

Although the pleomorphic adenoma in palate has a good prognosis, determinants regarding its clinical behavior when recurrence or malignant transformation occur are unclear77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
,1414 Choi SY, Choi J, Hwang I, Cho J, Ko YH, Jeong HS. Comparative Longitudinal Analysis of Malignant Transformation in Pleomorphic Adenoma and Recurrent Pleomorphic Adenoma. J Clin Med. 2022;11(7):1808. https://doi.org/10.3390/jcm11071808
https://doi.org/10.3390/jcm11071808...
,1515 Lopes MA, Kowalski LP, Santos GDC, De Almeida OP. A clinicopathologic study of 196 intraoral minor salivary gland tumours. J Oral Pathol Med. 1999;28(6):264–7. https://doi.org/10.1111/j.1600-0714.1999.tb02036.x
https://doi.org/10.1111/j.1600-0714.1999...
. Thus, the aim of this systematic review was to analyze the case reports of RPA to detect potential factors that influence the recurrence, clinical behavior, and the odds of malignancy of this tumor in palate.

Methods

The scientific question addressed by this study was: what are the factors that influence the clinical behavior of palatal pleomorphic adenoma that relapsed or underwent malignant transformation after the treatment? This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 statement guidelines1919 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. https://doi.org/10.1136/bmj.n71
https://doi.org/10.1136/bmj.n71...
. The protocol was registered in International Prospective Register of Systematic Review (PROSPERO) database under the number CRD42023398419.

Eligibility criteria

The inclusion criteria followed the Patient, Intervention, Comparison, Outcome, and Study design (PICOS) strategy, as follows:

  • Population: patients with recurrent pleomorphic adenoma arising in the palate;

  • Intervention: clinicopathological features of the patients, treatment and time of tumor recurrence;

  • Comparison: none;

  • Outcome measures: tumor recurrence after treatment of primary tumor in the palate (with or without malignant transformation);

  • Types of study: cross-sectional studies, case series, case reports, letters to the editor, short communications.

The exclusion criteria were:

  • Studies reporting RPA in anatomic sites other than palate or without description of histopathological confirmation;

  • pre-clinical and in-vitro studies;

  • Clinical studies or cases series of RPA lacking key information about clinicopathological features individualized of the patients, treatment, or clinical outcome of patient.

Information sources and search strategy

The literature search was carried out in the following electronic databases: PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, and EMBASE. In addition, the grey literature was also queried manually using the databases Virtual Health Library, OpenGrey, and Google Scholar (the 100 first results). The search strategy was adapted for each database (Suppl. Mat. 1). All searches were performed on March 20th, 2023. There were no limitations on the language and year of publication of the articles.

Study selection

All studies retrieved were imported into the reference management tool EndNote Web (EndNote Web; Thomson Reuters Inc., Philadelphia, PA, United States of America), and the duplicates were excluded. The authors conducted a thorough review of previous findings to confirm adherence to the inclusion criteria. In the first phase of the study selection, two independent reviewers analyzed the titles and abstracts of the studies to screen the relevant articles. Any disagreements were resolved by discussion, and an expert in oral pathology was consulted when necessary. In the second phase, the same reviewers read the full texts of the studies selected in the phase 1 regardless applying the inclusion and exclusion criteria. If there were any disagreements, the expert was consulted.

Data extraction

Two authors extracted the relevant information of the studies into a spreadsheet. Data collected included: study design, country, number of patients, demographic characteristics of patients (sex and age), clinicopathological features of the tumor (clinical description, size, anatomic location, imaging exams, and treatment), and clinical outcome (time of recurrence after the initial treatment and/or malignant transformation). All data was consistently coded across all studies.

Risk of bias assessment

The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for case reports was utilized to evaluate the risk of bias of the individual studies2020 Aromataris E, Munn Z. JBI Manual for Evidence Synthesis. JBI; 2020. https://doi.org/10.46658/JBIMES-20-01
https://doi.org/10.46658/JBIMES-20-01...
. The JBI checklist included questions regarding the patient demographics, clinical history and presentation, diagnostic assessments, treatments, post-treatment condition, adverse events, and key takeaway points. The assessments were conducted independently by two reviewers. Any disagreements were resolved by consensus, and a third reviewer was consulted when necessary.

Synthesis methods

All statistical analyses were performed using the Statistical Package for Social Sciences, Version 26.0 (Chicago, IL, United States of America), and GraphPad Prism version 8.0 (GraphPad Software, San Diego, CA, United States of America).

The clinical features of patients with RPA in palate were reported in frequency of cases, percentages, mean of ages, mean of tumor recurrence time, and mean of malignancy time. A binomial logistic regression was performed to assess the odds ratio (OR) of detecting recurrence at one, five, 10, and 20 years after treatment of primary pleomorphic adenoma (categorical variables). The confidence interval (CI) was set at 95%. The association between the mean tumor recurrence time and malignancy was verified by Fisher’s exact test. Values of p < 0.05 were considered significant for all statistic tests.

Results

Study selection

The electronic search returned the total of 2,365 articles. After duplicates removal, 336 manuscripts were screened based on their titles and abstracts. Thirteen articles met the eligibility criteria and were selected for full-text analysis. All 13 articles fulfilled the inclusion criteria and were included in this review: two retrospective studies2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
,2222 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...
, 10 case reports2323 Byars LT, Ackerman LV, Peacock E. Tumors of salivary gland origin in children: a clinical pathologic appraisal of 24 cases. Ann Surg. 1957;146(1):40–51. https://doi.org/10.1097/00000658-195707000-00005
https://doi.org/10.1097/00000658-1957070...

24 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...

25 Shaaban H, Bruce J, Davenport PJ. Recurrent pleomorphic adenoma of the palate in a child. Br J Plast Surg. 2001;54(3):245–7. https://doi.org/10.1054/bjps.2000.3536
https://doi.org/10.1054/bjps.2000.3536...

26 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...

27 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...

28 Berardi D, Scoccia A, Perfetti G, Berardi S. Recurrence of pleomorphic adenoma of the palate after sixteen years: case report and an analysis of the literature. J Biol Regul Homeost Agents. 2009;23(4):225–9.

29 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...

30 Lima FF, Bezerra CP, Rocha AC, Martins IS, Bernaola-Paredes WE. Surgical Management of Palatal Pleomorphic Adenoma (PPA) Recurrence After 10 years, Treated at a Brazilian Center - A Case Report. Ann Maxillofac Surg. 2020;10(2):533–6. https://doi.org/10.4103/ams.ams_107_20
https://doi.org/10.4103/ams.ams_107_20...

31 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...
-3232 Hemavathy K, Giri GVV, Subramani V, Susruthan M. Recurrent Palatal Pleomorphic Adenoma: A Case Report With a Long-Term Follow-Up. Cureus. 2022;14(6):e26363. https://doi.org/10.7759%2Fcureus.26363
https://doi.org/10.7759%2Fcureus.26363...
, and one letter to the editor3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
. All 13 studies were published in English, between 1957 and 2022, and were conducted in United Kingdom2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
,2525 Shaaban H, Bruce J, Davenport PJ. Recurrent pleomorphic adenoma of the palate in a child. Br J Plast Surg. 2001;54(3):245–7. https://doi.org/10.1054/bjps.2000.3536
https://doi.org/10.1054/bjps.2000.3536...
,3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
, India2929 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...
,3232 Hemavathy K, Giri GVV, Subramani V, Susruthan M. Recurrent Palatal Pleomorphic Adenoma: A Case Report With a Long-Term Follow-Up. Cureus. 2022;14(6):e26363. https://doi.org/10.7759%2Fcureus.26363
https://doi.org/10.7759%2Fcureus.26363...
, United States2222 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...
,2323 Byars LT, Ackerman LV, Peacock E. Tumors of salivary gland origin in children: a clinical pathologic appraisal of 24 cases. Ann Surg. 1957;146(1):40–51. https://doi.org/10.1097/00000658-195707000-00005
https://doi.org/10.1097/00000658-1957070...
, Japan2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
, Greece2626 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...
, Iran2727 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...
, Italy2828 Berardi D, Scoccia A, Perfetti G, Berardi S. Recurrence of pleomorphic adenoma of the palate after sixteen years: case report and an analysis of the literature. J Biol Regul Homeost Agents. 2009;23(4):225–9. , South Africa3131 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...
, and Brazil3030 Lima FF, Bezerra CP, Rocha AC, Martins IS, Bernaola-Paredes WE. Surgical Management of Palatal Pleomorphic Adenoma (PPA) Recurrence After 10 years, Treated at a Brazilian Center - A Case Report. Ann Maxillofac Surg. 2020;10(2):533–6. https://doi.org/10.4103/ams.ams_107_20
https://doi.org/10.4103/ams.ams_107_20...
. The flowchart shows the selection process (Fig. 1).

Figure 1
Flowchart screening the steps for the articles included in this systematic review.

Characteristics of the included studies

The characteristics of the 13 included studies are summarized in Table 1. The sample included 18 patients with RPA in palate. Regarding gender, 11 (61.1%) patients were females and seven (38.9%) males. The mean age of patients with RPA was 49.3 years old (range 9–73 years old). In patients who developed RPA, the mean age of the primary tumor was 33 years old (range 4–68).

Table 1
Summary of the main clinicopathological characteristics of the patients with recurrent pleomorphic adenoma included in this systematic literature review.

RPA in the palate was clinically characterized as a painless, solitary well-defined and firm nodule, usually measuring up to 3 cm in diameter2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
,2222 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...
,2828 Berardi D, Scoccia A, Perfetti G, Berardi S. Recurrence of pleomorphic adenoma of the palate after sixteen years: case report and an analysis of the literature. J Biol Regul Homeost Agents. 2009;23(4):225–9.

29 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...

30 Lima FF, Bezerra CP, Rocha AC, Martins IS, Bernaola-Paredes WE. Surgical Management of Palatal Pleomorphic Adenoma (PPA) Recurrence After 10 years, Treated at a Brazilian Center - A Case Report. Ann Maxillofac Surg. 2020;10(2):533–6. https://doi.org/10.4103/ams.ams_107_20
https://doi.org/10.4103/ams.ams_107_20...

31 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...

32 Hemavathy K, Giri GVV, Subramani V, Susruthan M. Recurrent Palatal Pleomorphic Adenoma: A Case Report With a Long-Term Follow-Up. Cureus. 2022;14(6):e26363. https://doi.org/10.7759%2Fcureus.26363
https://doi.org/10.7759%2Fcureus.26363...
-3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
. The tumor was often covered by normal-colored oral mucosa with occasional superficial ulceration2525 Shaaban H, Bruce J, Davenport PJ. Recurrent pleomorphic adenoma of the palate in a child. Br J Plast Surg. 2001;54(3):245–7. https://doi.org/10.1054/bjps.2000.3536
https://doi.org/10.1054/bjps.2000.3536...
. The presence of bone involvement was reported in nine cases2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
,2222 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...
,2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
,2929 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...
,3131 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...
,3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
. In most of patients, the magnetic resonance imaging or cone-beam computed tomography revealed a hypodense maxillary lesion, sometimes with irregular margins and extending to the maxillary sinus, nasal, and orbital cavity2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
,2222 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...
,2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
,2929 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...
,3131 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...

32 Hemavathy K, Giri GVV, Subramani V, Susruthan M. Recurrent Palatal Pleomorphic Adenoma: A Case Report With a Long-Term Follow-Up. Cureus. 2022;14(6):e26363. https://doi.org/10.7759%2Fcureus.26363
https://doi.org/10.7759%2Fcureus.26363...
-3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
.

Clinical outcome

The tumor recurrence time ranged from two to 41 years (mean 16.3 years) after treatment of the primary pleomorphic adenoma in the palate. The surgical removal was the treatment of choice in all cases2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
,2222 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...
,2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...

25 Shaaban H, Bruce J, Davenport PJ. Recurrent pleomorphic adenoma of the palate in a child. Br J Plast Surg. 2001;54(3):245–7. https://doi.org/10.1054/bjps.2000.3536
https://doi.org/10.1054/bjps.2000.3536...

26 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...

27 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...

28 Berardi D, Scoccia A, Perfetti G, Berardi S. Recurrence of pleomorphic adenoma of the palate after sixteen years: case report and an analysis of the literature. J Biol Regul Homeost Agents. 2009;23(4):225–9.

29 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...

30 Lima FF, Bezerra CP, Rocha AC, Martins IS, Bernaola-Paredes WE. Surgical Management of Palatal Pleomorphic Adenoma (PPA) Recurrence After 10 years, Treated at a Brazilian Center - A Case Report. Ann Maxillofac Surg. 2020;10(2):533–6. https://doi.org/10.4103/ams.ams_107_20
https://doi.org/10.4103/ams.ams_107_20...

31 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...

32 Hemavathy K, Giri GVV, Subramani V, Susruthan M. Recurrent Palatal Pleomorphic Adenoma: A Case Report With a Long-Term Follow-Up. Cureus. 2022;14(6):e26363. https://doi.org/10.7759%2Fcureus.26363
https://doi.org/10.7759%2Fcureus.26363...
-3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
. Two cases, that were managed with radiotherapy following the surgery of the primary tumor, underwent malignant transformation2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
.

Four out of the 18 patients with RPA in the palate underwent malignant transformation2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
,2626 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...
,2727 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...
. Therefore, the malignant transformation rate among patients with RPA was 22.2%, and the time of tumor progression before the malignancy diagnosis ranged from two to 36 years (mean of 23 years). The malignant transformation of RPA in palate occurred 30 years after the primary tumor removal, in three out of the four patients. Among the four patients with RPA who developed malignant tumors, only one developed a tumor of mesenchymal origin, specifically chondrosarcoma2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
, whereas the remaining three patients developed tumors of epithelial origin, including one clear cell carcinoma2727 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...
, one carcinoma of ductal type2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
, and one low-grade malignant myoepithelial carcinoma2626 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...
. All patients with malignant tumors were treated with surgery2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
,2626 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...
, and adjuvant radiotherapy was performed in two patients2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
(Table 1).

Risk of bias in studies

The results of the risk of bias of cases reports of RPA included are available as supplementary data (see Data Availability Statement section). Six studies demonstrated low risk of bias2525 Shaaban H, Bruce J, Davenport PJ. Recurrent pleomorphic adenoma of the palate in a child. Br J Plast Surg. 2001;54(3):245–7. https://doi.org/10.1054/bjps.2000.3536
https://doi.org/10.1054/bjps.2000.3536...
,2626 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...
,2828 Berardi D, Scoccia A, Perfetti G, Berardi S. Recurrence of pleomorphic adenoma of the palate after sixteen years: case report and an analysis of the literature. J Biol Regul Homeost Agents. 2009;23(4):225–9. ,3030 Lima FF, Bezerra CP, Rocha AC, Martins IS, Bernaola-Paredes WE. Surgical Management of Palatal Pleomorphic Adenoma (PPA) Recurrence After 10 years, Treated at a Brazilian Center - A Case Report. Ann Maxillofac Surg. 2020;10(2):533–6. https://doi.org/10.4103/ams.ams_107_20
https://doi.org/10.4103/ams.ams_107_20...

31 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...
-3232 Hemavathy K, Giri GVV, Subramani V, Susruthan M. Recurrent Palatal Pleomorphic Adenoma: A Case Report With a Long-Term Follow-Up. Cureus. 2022;14(6):e26363. https://doi.org/10.7759%2Fcureus.26363
https://doi.org/10.7759%2Fcureus.26363...
, six studies demonstrated unclear risk of bias2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
,2323 Byars LT, Ackerman LV, Peacock E. Tumors of salivary gland origin in children: a clinical pathologic appraisal of 24 cases. Ann Surg. 1957;146(1):40–51. https://doi.org/10.1097/00000658-195707000-00005
https://doi.org/10.1097/00000658-1957070...
,2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...
,2727 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...
,2929 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...
,3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
, and one study demonstrated high risk of bias2222 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...
.

Results of quantitative synthesis

The OR of detecting a recurrence 10 and 20 years after the treatment of the primary pleomorphic adenoma was 5.57 (95%CI 1.13–27.52) and 18.78 (95%CI 3.18–110.84) times higher than at the one-year follow-up time, respectively (Fig. 2).

Figure 2
The odds for detecting primary pleomorphic adenoma recurrence over time. Bold values denote statistical significance.

No statistically significant association was detected between mean time of tumor recurrence (< 16 years or ≥ 16 years) and malignant transformation (p = 0.5865). However, the recurrence of three out of four palatal pleomorphic adenoma that underwent malignant transformation occurred after 30 years of the primary tumor.

Discussion

Due to the rarity of minor salivary gland pleomorphic adenomas, only a limited number of well-documented RPA was found2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...

22 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...

23 Byars LT, Ackerman LV, Peacock E. Tumors of salivary gland origin in children: a clinical pathologic appraisal of 24 cases. Ann Surg. 1957;146(1):40–51. https://doi.org/10.1097/00000658-195707000-00005
https://doi.org/10.1097/00000658-1957070...

24 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...

25 Shaaban H, Bruce J, Davenport PJ. Recurrent pleomorphic adenoma of the palate in a child. Br J Plast Surg. 2001;54(3):245–7. https://doi.org/10.1054/bjps.2000.3536
https://doi.org/10.1054/bjps.2000.3536...

26 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...

27 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...

28 Berardi D, Scoccia A, Perfetti G, Berardi S. Recurrence of pleomorphic adenoma of the palate after sixteen years: case report and an analysis of the literature. J Biol Regul Homeost Agents. 2009;23(4):225–9.

29 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...

30 Lima FF, Bezerra CP, Rocha AC, Martins IS, Bernaola-Paredes WE. Surgical Management of Palatal Pleomorphic Adenoma (PPA) Recurrence After 10 years, Treated at a Brazilian Center - A Case Report. Ann Maxillofac Surg. 2020;10(2):533–6. https://doi.org/10.4103/ams.ams_107_20
https://doi.org/10.4103/ams.ams_107_20...

31 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...

32 Hemavathy K, Giri GVV, Subramani V, Susruthan M. Recurrent Palatal Pleomorphic Adenoma: A Case Report With a Long-Term Follow-Up. Cureus. 2022;14(6):e26363. https://doi.org/10.7759%2Fcureus.26363
https://doi.org/10.7759%2Fcureus.26363...
-3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
. To fill this gap, this systematic literature review was conducted to investigate the clinical behavior and odds of malignancy of RPA arising in the palate.

The demographic factors of RPA found in this review was in accordance with other studies77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
,88 Rooker SA, Van Abel KM, Yin LX, Nagelschneider AA, Price DL, Olsen KD, Janus JR, Kasperbauer JL, Moore EJ. Risk factors for subsequent recurrence after surgical treatment of recurrent pleomorphic adenoma of the parotid gland. Head Neck. 2021;43(4):1088–96. https://doi.org/10.1002/hed.26570
https://doi.org/10.1002/hed.26570...
,3434 Malard O, Wagner R, Joubert M, Delemazure AS, Rio E, Durand N, Espitalier F. Prognostic factors for secondary recurrence of pleomorphic adenoma: a 20-year, retrospective study. J Laryngol Otol. 2013;127(9):902–7. https://doi.org/10.1017/s0022215113001801
https://doi.org/10.1017/s002221511300180...
,3535 Witt RL, Eisele DW, Morton RP, Nicolai P, Poorten V Vander, Zbären P. Etiology and management of recurrent parotid pleomorphic adenoma. Laryngoscope. 2015;125(4):888–93. https://doi.org/10.1002/lary.24964
https://doi.org/10.1002/lary.24964...
: the tumor occurred mainly in women (61.1%), and the average age of patients was 49.3 years old, contrasting only with one study that found higher frequency of RPA in men than women3636 Patigaroo SA, Patigaroo FA, Ashraf J, Mehfooz N, Shakeel M, Khan NA, Kirmani MH. Pleomorphic Adenoma of Hard Palate: An Experience. J Maxillofac Oral Surg. 2014;13(1):36–41. https://doi.org/10.1007%2Fs12663-012-0448-5
https://doi.org/10.1007%2Fs12663-012-044...
. The patients with RPA were younger at time of diagnosis of the primary pleomorphic adenoma (mean 33 years old – four patients were < 20 years old and six patients were in their twenties), reinforcing the incidence of palatal benign minor salivary gland at earlier age11 Almeslet AS. Pleomorphic Adenoma: A Systematic Review. Int J Clin Pediatr Dent. 2020;13(3):284–7. https://doi.org/10.5005/jp-journals-10005-1776
https://doi.org/10.5005/jp-journals-1000...

2 Bruzinga FFB, Fernandes FCF, Dias FR, Lima MG, de Souza PEA, de Aguiar MCF, Grossmann S de MC. Clinical and demographic features of minor salivary gland tumors: A collaborative study of 480 cases. Oral Dis. 2023;29(3):1028–38. https://doi.org/10.1111/odi.14119
https://doi.org/10.1111/odi.14119...
-33 Wu YC, Wang YP, Cheng SJ, Chen HM, Sun A, Chang JYF. Clinicopathological study of 74 palatal pleomorphic adenomas. J Formos Med Assoc. 2016;115(1):25–30. https://doi.org/10.1016/j.jfma.2015.09.008
https://doi.org/10.1016/j.jfma.2015.09.0...
,66 Alsufyani NA, Altowaijri AA, Alshehri BM, Alsadhan MS. Systematic Review of Clinical and Radiographic Signs of Pediatric Pleomorphic Adenoma of Minor Salivary Glands. J Contemp Dent Pract [Internet]. 2021 [cited 2023 May 2];22(9):1063–8. Available from: https://pubmed.ncbi.nlm.nih.gov/35000954/
https://pubmed.ncbi.nlm.nih.gov/35000954...
,88 Rooker SA, Van Abel KM, Yin LX, Nagelschneider AA, Price DL, Olsen KD, Janus JR, Kasperbauer JL, Moore EJ. Risk factors for subsequent recurrence after surgical treatment of recurrent pleomorphic adenoma of the parotid gland. Head Neck. 2021;43(4):1088–96. https://doi.org/10.1002/hed.26570
https://doi.org/10.1002/hed.26570...
,3636 Patigaroo SA, Patigaroo FA, Ashraf J, Mehfooz N, Shakeel M, Khan NA, Kirmani MH. Pleomorphic Adenoma of Hard Palate: An Experience. J Maxillofac Oral Surg. 2014;13(1):36–41. https://doi.org/10.1007%2Fs12663-012-0448-5
https://doi.org/10.1007%2Fs12663-012-044...
.

Clinically, the RPA on the palate were small, firm, and smooth nodules, asymptomatic, often covered by normal oral mucosa, and measuring up to 3 cm in diameter2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
,2222 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...
,2828 Berardi D, Scoccia A, Perfetti G, Berardi S. Recurrence of pleomorphic adenoma of the palate after sixteen years: case report and an analysis of the literature. J Biol Regul Homeost Agents. 2009;23(4):225–9.

29 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...

30 Lima FF, Bezerra CP, Rocha AC, Martins IS, Bernaola-Paredes WE. Surgical Management of Palatal Pleomorphic Adenoma (PPA) Recurrence After 10 years, Treated at a Brazilian Center - A Case Report. Ann Maxillofac Surg. 2020;10(2):533–6. https://doi.org/10.4103/ams.ams_107_20
https://doi.org/10.4103/ams.ams_107_20...

31 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...

32 Hemavathy K, Giri GVV, Subramani V, Susruthan M. Recurrent Palatal Pleomorphic Adenoma: A Case Report With a Long-Term Follow-Up. Cureus. 2022;14(6):e26363. https://doi.org/10.7759%2Fcureus.26363
https://doi.org/10.7759%2Fcureus.26363...
-3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
, confirming the pattern well-established of the slow growing for this tumor in this location33 Wu YC, Wang YP, Cheng SJ, Chen HM, Sun A, Chang JYF. Clinicopathological study of 74 palatal pleomorphic adenomas. J Formos Med Assoc. 2016;115(1):25–30. https://doi.org/10.1016/j.jfma.2015.09.008
https://doi.org/10.1016/j.jfma.2015.09.0...
,3737 Moon SY. Surgical Management of the Palatal Pleomorphic Adenoma. J Craniofac Surg. 2019;30(6):e580–2. https://doi.org/10.1097/scs.0000000000005608
https://doi.org/10.1097/scs.000000000000...
,3838 Gupta P, Gupta M. Rare Case Report: Young Male Hard Palate Pleomorphic Adenoma. Indian J Otolaryngol Head Neck Surg. 2021;73(4):510–3. https://doi.org/10.1007/s12070-020-01887-w
https://doi.org/10.1007/s12070-020-01887...
. Imaging examinations consistently showed a hypodense maxillary lesion, often with well-defined borders, extending into the maxillary sinus, nasal cavity, and orbital cavity. Additionally, bone involvement was also observed2626 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...
,2727 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...
,2929 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...
,3434 Malard O, Wagner R, Joubert M, Delemazure AS, Rio E, Durand N, Espitalier F. Prognostic factors for secondary recurrence of pleomorphic adenoma: a 20-year, retrospective study. J Laryngol Otol. 2013;127(9):902–7. https://doi.org/10.1017/s0022215113001801
https://doi.org/10.1017/s002221511300180...
,3636 Patigaroo SA, Patigaroo FA, Ashraf J, Mehfooz N, Shakeel M, Khan NA, Kirmani MH. Pleomorphic Adenoma of Hard Palate: An Experience. J Maxillofac Oral Surg. 2014;13(1):36–41. https://doi.org/10.1007%2Fs12663-012-0448-5
https://doi.org/10.1007%2Fs12663-012-044...
,3838 Gupta P, Gupta M. Rare Case Report: Young Male Hard Palate Pleomorphic Adenoma. Indian J Otolaryngol Head Neck Surg. 2021;73(4):510–3. https://doi.org/10.1007/s12070-020-01887-w
https://doi.org/10.1007/s12070-020-01887...
. These clinical features align with descriptions found in other studies of primary pleomorphic adenoma in the palate33 Wu YC, Wang YP, Cheng SJ, Chen HM, Sun A, Chang JYF. Clinicopathological study of 74 palatal pleomorphic adenomas. J Formos Med Assoc. 2016;115(1):25–30. https://doi.org/10.1016/j.jfma.2015.09.008
https://doi.org/10.1016/j.jfma.2015.09.0...
,3737 Moon SY. Surgical Management of the Palatal Pleomorphic Adenoma. J Craniofac Surg. 2019;30(6):e580–2. https://doi.org/10.1097/scs.0000000000005608
https://doi.org/10.1097/scs.000000000000...
.

The pleomorphic adenoma on the palate is typically treated with surgical resection, which results in low rate of local recurrence33 Wu YC, Wang YP, Cheng SJ, Chen HM, Sun A, Chang JYF. Clinicopathological study of 74 palatal pleomorphic adenomas. J Formos Med Assoc. 2016;115(1):25–30. https://doi.org/10.1016/j.jfma.2015.09.008
https://doi.org/10.1016/j.jfma.2015.09.0...
,66 Alsufyani NA, Altowaijri AA, Alshehri BM, Alsadhan MS. Systematic Review of Clinical and Radiographic Signs of Pediatric Pleomorphic Adenoma of Minor Salivary Glands. J Contemp Dent Pract [Internet]. 2021 [cited 2023 May 2];22(9):1063–8. Available from: https://pubmed.ncbi.nlm.nih.gov/35000954/
https://pubmed.ncbi.nlm.nih.gov/35000954...
. In this systematic review, all RPA were treated by surgical resection2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
,2222 Ritwik P, Brannon RB. A clinical analysis of nine new pediatric and adolescent cases of benign minor salivary gland neoplasms and a review of the literature. J Med Case Rep. 2012;6:287. https://doi.org/10.1186%2F1752-1947-6-287
https://doi.org/10.1186%2F1752-1947-6-28...
,2424 Hellquist H, Michaels L. Malignant mixed tumour. A salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch A Pathol Anat Histopathol. 1986;409(1):93–103. https://doi.org/10.1007/bf00705409
https://doi.org/10.1007/bf00705409...

25 Shaaban H, Bruce J, Davenport PJ. Recurrent pleomorphic adenoma of the palate in a child. Br J Plast Surg. 2001;54(3):245–7. https://doi.org/10.1054/bjps.2000.3536
https://doi.org/10.1054/bjps.2000.3536...

26 Karatzanis AD, Drivas EI, Giannikaki ES, Lachanas VA, Hatziioannou JK, Velegrakis GA. Malignant myoepithelioma arising from recurrent pleomorphic adenoma of the soft palate. Auris Nasus Larynx. 2005;32(4):435–7. https://doi.org/10.1016/j.anl.2005.04.001
https://doi.org/10.1016/j.anl.2005.04.00...

27 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...

28 Berardi D, Scoccia A, Perfetti G, Berardi S. Recurrence of pleomorphic adenoma of the palate after sixteen years: case report and an analysis of the literature. J Biol Regul Homeost Agents. 2009;23(4):225–9.

29 Faisal M, Mishra S. A Case of Massive Recurrent Pleomorphic Adenoma of the Palate. J Dent Oral Disord [Internet]. 2016 [cited 2023 Mar 23];2(8):1041. Available from: https://austinpublishinggroup.com/dental-disorders/fulltext/jdod-v2-id1041.php
https://austinpublishinggroup.com/dental...

30 Lima FF, Bezerra CP, Rocha AC, Martins IS, Bernaola-Paredes WE. Surgical Management of Palatal Pleomorphic Adenoma (PPA) Recurrence After 10 years, Treated at a Brazilian Center - A Case Report. Ann Maxillofac Surg. 2020;10(2):533–6. https://doi.org/10.4103/ams.ams_107_20
https://doi.org/10.4103/ams.ams_107_20...

31 Nokaneng EN. Invasive recurrent pleomorphic adenoma of the palate: A case report and literature review. Oral Maxillofac Surg Cases. 2022;8(4):100281. https://doi.org/10.1016/j.omsc.2022.100281
https://doi.org/10.1016/j.omsc.2022.1002...

32 Hemavathy K, Giri GVV, Subramani V, Susruthan M. Recurrent Palatal Pleomorphic Adenoma: A Case Report With a Long-Term Follow-Up. Cureus. 2022;14(6):e26363. https://doi.org/10.7759%2Fcureus.26363
https://doi.org/10.7759%2Fcureus.26363...
-3333 Turner MJA, Smith WP. An exceptionally late recurrence of pleomorphic adenoma. J Oral Maxillofac Surg. 2006;64(9):1460. https://doi.org/10.1016/j.joms.2006.05.012
https://doi.org/10.1016/j.joms.2006.05.0...
. Of note, the two cases that received adjuvant radiotherapy were treated back in 1986 and underwent malignant transformation. Adjuvant radiotherapy is no longer indicated for benign tumors as it may delay but not prevent recurrence1717 Alzumaili B, Xu B, Saliba M, Abuhashem A, Ganly I, Ghossein R, Katabi N. Clinicopathologic characteristics and prognostic factors of primary and recurrent pleomorphic adenoma a single institution retrospective study of 705 cases. Am J Surg Pathol. 2022;46(6):854–62. https://doi.org/10.1097/pas.0000000000001837
https://doi.org/10.1097/pas.000000000000...
,3434 Malard O, Wagner R, Joubert M, Delemazure AS, Rio E, Durand N, Espitalier F. Prognostic factors for secondary recurrence of pleomorphic adenoma: a 20-year, retrospective study. J Laryngol Otol. 2013;127(9):902–7. https://doi.org/10.1017/s0022215113001801
https://doi.org/10.1017/s002221511300180...
.

Some factors associated with the recurrence of pleomorphic adenoma in different studies, based mainly in parotid gland, were correlated with clinical features of patients and incomplete surgical resection of tumor77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
,99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
,1414 Choi SY, Choi J, Hwang I, Cho J, Ko YH, Jeong HS. Comparative Longitudinal Analysis of Malignant Transformation in Pleomorphic Adenoma and Recurrent Pleomorphic Adenoma. J Clin Med. 2022;11(7):1808. https://doi.org/10.3390/jcm11071808
https://doi.org/10.3390/jcm11071808...
. Previous studies proposed that the higher incidence of primary or recurrent pleomorphic adenoma in women could be associated with higher levels of estrogen99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
,3434 Malard O, Wagner R, Joubert M, Delemazure AS, Rio E, Durand N, Espitalier F. Prognostic factors for secondary recurrence of pleomorphic adenoma: a 20-year, retrospective study. J Laryngol Otol. 2013;127(9):902–7. https://doi.org/10.1017/s0022215113001801
https://doi.org/10.1017/s002221511300180...
. Nevertheless, more studies are required to support the hormonal influence in benign tumor arising from salivary gland. The lack of information about surgical margin in the primary pleomorphic adenoma on the palate was one of the limitations in the present review, not allowing us to analyze the influence of this critical factor on tumor recurrence.

Currently, the time of tumor incubation has gained strength as one of the most determining factors in the recurrence and/or malignant transformation of pleomorphic adenoma77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
,99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
,1414 Choi SY, Choi J, Hwang I, Cho J, Ko YH, Jeong HS. Comparative Longitudinal Analysis of Malignant Transformation in Pleomorphic Adenoma and Recurrent Pleomorphic Adenoma. J Clin Med. 2022;11(7):1808. https://doi.org/10.3390/jcm11071808
https://doi.org/10.3390/jcm11071808...
. This systematic review showed a mean tumor recurrence time of 16.3 years and a mean time of malignant transformation of pleomorphic adenoma of 24.5 years. The recurrence of benign pleomorphic adenoma has been attributed to the presence of microscopic residual disease, primarily resulting from incomplete surgical resection or a contaminated surgical field33 Wu YC, Wang YP, Cheng SJ, Chen HM, Sun A, Chang JYF. Clinicopathological study of 74 palatal pleomorphic adenomas. J Formos Med Assoc. 2016;115(1):25–30. https://doi.org/10.1016/j.jfma.2015.09.008
https://doi.org/10.1016/j.jfma.2015.09.0...
,77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
,99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
,3737 Moon SY. Surgical Management of the Palatal Pleomorphic Adenoma. J Craniofac Surg. 2019;30(6):e580–2. https://doi.org/10.1097/scs.0000000000005608
https://doi.org/10.1097/scs.000000000000...
. Conversely, the transformation into malignancy is likely driven by inherent tumor factors as cytological and genetic alterations2121 Yasumoto M, Sunaba K, Shibuya H, Kurabayashi T. Recurrent pleomorphic adenoma of the head and neck. Neuroradiology. 1999;41(4):300–4. https://doi.org/10.1007/s002340050752
https://doi.org/10.1007/s002340050752...
and this process is time-dependent1414 Choi SY, Choi J, Hwang I, Cho J, Ko YH, Jeong HS. Comparative Longitudinal Analysis of Malignant Transformation in Pleomorphic Adenoma and Recurrent Pleomorphic Adenoma. J Clin Med. 2022;11(7):1808. https://doi.org/10.3390/jcm11071808
https://doi.org/10.3390/jcm11071808...
, confirming the finding of this systematic review. It is important to reinforce that most studies of malignant transformation have focused on samples from pleomorphic adenoma arising from major salivary glands in large medical centers1111 Dimitrijevic MV, Boricic IV, Tomanović NR, Dimitrijevic AM, Bjelogrlić GM, Krstić AM, Stojkovic GM, Rajovic NZ, Djordjevic IPM, Djurkovic PM. Clinicopathological Analysis of 907 Major and Minor Salivary Gland Tumors. J Craniofac Surg. 2022;33(5):E507–9. https://doi.org/10.1097/scs.0000000000008482
https://doi.org/10.1097/scs.000000000000...
.

Due to the low rate of recurrence and the benign nature of the tumor, long-term patient follow-up is not commonly practiced77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
,99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
. Consequently, most studies about RPA were small series and lacked comprehensive information regarding primary lesion (e.g., treatment type, histological features, and surgical margins status)77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
. We found that the average time for tumor recurrence was 16.3 months after primary tumor removal, an average slightly lower than those found by other ones77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...

8 Rooker SA, Van Abel KM, Yin LX, Nagelschneider AA, Price DL, Olsen KD, Janus JR, Kasperbauer JL, Moore EJ. Risk factors for subsequent recurrence after surgical treatment of recurrent pleomorphic adenoma of the parotid gland. Head Neck. 2021;43(4):1088–96. https://doi.org/10.1002/hed.26570
https://doi.org/10.1002/hed.26570...
-99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
. The odds of detecting a recurrence at 10 and 20 years after primary tumor were 5.57 and 18.78 times higher than at the one-year follow-up time. These results are consistent with other studies suggesting that the length of time the lesion incubates in patients may be associated with recurrence33 Wu YC, Wang YP, Cheng SJ, Chen HM, Sun A, Chang JYF. Clinicopathological study of 74 palatal pleomorphic adenomas. J Formos Med Assoc. 2016;115(1):25–30. https://doi.org/10.1016/j.jfma.2015.09.008
https://doi.org/10.1016/j.jfma.2015.09.0...
,77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
,1414 Choi SY, Choi J, Hwang I, Cho J, Ko YH, Jeong HS. Comparative Longitudinal Analysis of Malignant Transformation in Pleomorphic Adenoma and Recurrent Pleomorphic Adenoma. J Clin Med. 2022;11(7):1808. https://doi.org/10.3390/jcm11071808
https://doi.org/10.3390/jcm11071808...
. However, in the present literature review, the difficulty in establish whether the pleomorphic adenoma was completely removed and the loss of follow-up of patients after tumor surgery raises the question whether these recurrences are a result of prolonged tumor incubation or the development of primary tumors in the same location.

The RPA on the palate can lead to malignant transformation, negatively impacting the patient’s prognosis66 Alsufyani NA, Altowaijri AA, Alshehri BM, Alsadhan MS. Systematic Review of Clinical and Radiographic Signs of Pediatric Pleomorphic Adenoma of Minor Salivary Glands. J Contemp Dent Pract [Internet]. 2021 [cited 2023 May 2];22(9):1063–8. Available from: https://pubmed.ncbi.nlm.nih.gov/35000954/
https://pubmed.ncbi.nlm.nih.gov/35000954...
,77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
,3434 Malard O, Wagner R, Joubert M, Delemazure AS, Rio E, Durand N, Espitalier F. Prognostic factors for secondary recurrence of pleomorphic adenoma: a 20-year, retrospective study. J Laryngol Otol. 2013;127(9):902–7. https://doi.org/10.1017/s0022215113001801
https://doi.org/10.1017/s002221511300180...
. In this systematic literature review of 18 cases of RPA, it was found that 22.2% progressed to malignant tumors, a rate considered high compared to other studies77 Valstar MH, Andreasen S, Bhairosing PA, McGurk M. Natural history of recurrent pleomorphic adenoma: implications on management. Head Neck. 2020;42(8):2058–66. https://doi.org/10.1002/hed.26137
https://doi.org/10.1002/hed.26137...
,99 Valstar MH, de Ridder M, van den Broek EC, Stuiver MM, van Dijk BAC, van Velthuysen MLF, Balm AJM, Smeele LE. Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence. Oral Oncol. 2017;66:93–9. https://doi.org/10.1016/j.oraloncology.2017.01.004
https://doi.org/10.1016/j.oraloncology.2...
,1212 Valstar MH, Mast H, ten Hove I, Moonen LR, Balm AJM, Smeele LE, Koljenović S, Dinjens WNM, van Velthuysen MLF. Malignant transformation of salivary gland pleomorphic adenoma: proof of principle. J Pathol Clin Res. 2021;7(5):432–7. https://doi.org/10.1002/cjp2.216
https://doi.org/10.1002/cjp2.216...
,3838 Gupta P, Gupta M. Rare Case Report: Young Male Hard Palate Pleomorphic Adenoma. Indian J Otolaryngol Head Neck Surg. 2021;73(4):510–3. https://doi.org/10.1007/s12070-020-01887-w
https://doi.org/10.1007/s12070-020-01887...
, probably associated with small tumor sample. The recent retrospective study by Choi et al.1414 Choi SY, Choi J, Hwang I, Cho J, Ko YH, Jeong HS. Comparative Longitudinal Analysis of Malignant Transformation in Pleomorphic Adenoma and Recurrent Pleomorphic Adenoma. J Clin Med. 2022;11(7):1808. https://doi.org/10.3390/jcm11071808
https://doi.org/10.3390/jcm11071808...
comparing malignancy and recurrence of pleomorphic adenoma found no evidence that relapse or repeated surgeries promote malignant transformation of the tumor. Notably, our analysis showed that most of the malignant transformation in the RPA occurred after 30 years of primary tumor removal, in line with other studies indicating a higher risk for malignization in long-standing tumors1313 Andreasen S, Therkildsen MH, Bjørndal K, Homøe P. Pleomorphic adenoma of the parotid gland 1985–2010: A Danish nationwide study of incidence, recurrence rate, and malignant transformation. Head Neck. 2016;38(Suppl. 1):E1364–9. https://doi.org/10.1002/hed.24228
https://doi.org/10.1002/hed.24228...
,1818 Key S, Chia C, Hasan Z, Sundaresan P, Dwivedi RC, Riffat F. Systematic review of prognostic factors in carcinoma ex pleomorphic adenoma. Oral Oncol. 2022;133:106052. https://doi.org/10.1016/j.oraloncology.2022.106052
https://doi.org/10.1016/j.oraloncology.2...
,2727 Negahban S, Daneshbod Y, Shishegar M. Clear cell carcinoma arising from pleomorphic adenoma of a minor salivary gland: Report of a case with fine needle aspiration, histologic and immunohistochemical findings. Acta Cytol. 2006;50(6):687–90. https://doi.org/10.1159/000326043
https://doi.org/10.1159/000326043...
.

The results of this systematic literature review are limited by sample size of RPA in palate, making certain statistical analyses unfeasible and producing possible discrepancies regarding the rate of malignant transformation of this tumor when compared to large minor salivary gland tumor series. Although there is a lack of information in some studies, the data available in this systematic review still suggest a series of coherent arguments. However, it is important to note that further evidence-based research regarding the clinical management of palatal recurrent pleomorphic adenoma is needed to fully evaluate the validity of these arguments.

Conclusion

The RPA in palate remains a rare event of late occurrence. It affects mainly middle-aged females and carries a risk of malignant transformation. Due to the lack of information, it was not possible to establish whether the recurrence of pleomorphic adenoma in palate was a result of prolonged tumor incubation or if the recurrence were, in fact, new primary tumor in the same location. Although uncommon, the patients with palatal pleomorphic adenoma should be warned about the possibility of recurrence or malignant transformation of tumor at advanced ages.

Acknowledgments

Not applicable.

  • Research performed at Postgraduate Program in Applied Dental Sciences, Bauru School of Dentistry, Universidade de São Paulo, Bauru (SP), Brazil.
  • Funding

    Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
    Finance code 001

Data availability statement

Supplementary data are available at:

https://zenodo.org/records/10600036

https://doi.org/10.5281/zenodo.10600035

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Edited by

Section editor: Sigmar Rode https://orcid.org/0000-0002-4261-4217

Publication Dates

  • Publication in this collection
    26 Feb 2024
  • Date of issue
    2024

History

  • Received
    19 Oct 2023
  • Accepted
    28 Nov 2023
Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia https://actacirbras.com.br/ - São Paulo - SP - Brazil
E-mail: actacirbras@gmail.com