The Laryngoscope C 2014 The American Laryngological, V
Rhinological and Otological Society, Inc.
Contemporary Review
Etiology and Management of Recurrent Parotid Pleomorphic Adenoma Robert Lee Witt, MD; David W. Eisele, MD; Randall P. Morton, MB, BS, MSc, FRACS; Piero Nicolai, MD; Vincent Vander Poorten, MD, PhD, MSc; Peter Zb€ aren, MD The objective of this review study was to encompass the relevant literature and current best practice options for this challenging, sometimes incurable problem. The source of the data was Ovid MEDLINE from 1946 to 2014. Review methods consisted of articles with clinical correlates. The most important cause of recurrence is enucleation with rupture and incomplete tumor excision at operation. Incomplete pseudocapsule, extracapsular extension, pseudopods of pleomorphic adenoma tissue, and satellite pleomorphic beyond the pseudocapsule are also likely linked to recurrent pleomorphic adenoma. Most recurrent pleomorphic adenoma are multinodular. Magnetic resonance imaging is the imaging study of choice for recurrent pleomorphic adenoma. Nerve integrity monitoring may reduce morbidity for recurrent pleomorphic adenoma. Treatment of recurrent pleomorphic adenoma must be individualized. Total parotidectomy, given the multicentricity of recurrent pleomorphic adenoma, is appropriate in many patients, but may be inadequate to control recurrent pleomorphic. There is accumulating evidence from retrospective series that postoperative radiation therapy results in significantly better local control. Key Words: pleomorphic adenoma, benign mixed tumor, recurrence, management, etiology. Level of Evidence: NA Laryngoscope, 00:000–000, 2014
INTRODUCTION Recurrence rates for pleomorphic adenoma (PA) are difficult to evaluate because of the small number of patients in most centers and the variability of follow-up. The predisposing factors for and management of recurrent pleomorphic adenoma (RPA) are varied. This contemporary review will encompass the relevant literature and current best practice options for this challenging, sometimes incurable problem.
METHODS An Ovid MEDLINE search was performed from January 1946 to April 2014 to identify English-language articles pub-
From the Department of Otolaryngology–Head & Neck Surgery (R.L.W.), Christiana Care/Thomas Jefferson University, Newark, Delaware, U.S.A.; Department of Otolaryngology–Head & Neck Surgery (D.W.E.), Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.; Department of Surgery (R.P.M.), University of Auckland; Department of Otolaryngology–Head & Neck Surgery (R.P.M.), CountiesManukau Health, University of Auckland, Auckland, New Zealand; Department of Otorhinolaryngology–Head and Neck Surgery (P.N.), University of Brescia, Brescia, Italy; Department of Otorhinolaryngology– Head and Neck Surgery (V.V.P.) and Department of Oncology (V.V.P.), Section Head & Neck Oncology, University Hospitals Leuven, Leuven, Belgium; Department of Otorhinolaryngology–Head and Neck Surgery (P.Z.), University Hospital Bern, Bern, Switzerland. Editor’s Note: This Manuscript was accepted for publication September 15, 2014. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Robert L. Witt, MD, 4745 OgletownStanton Rd, MAP #1, Suite 112, Newark, DE 19713. E-mail [email protected] DOI: 10.1002/lary.24964
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lished about RPA. A combination of relevant Medical Subject Headings, keywords, and limits were used in the search strategies. To broaden the abstract search, using keyword variation of parotid and recurrent, inclusion was not limited to etiology and management. To narrow the articles reviewed, abstracts were excluded if not pertaining to RPA. Various methods of parotidectomy are described in the literature, often interchangeably. Enucleation and extracapsular dissection do not dissect the facial nerve. Enucleation violates the capsule, whereas extracapsular dissection does not. Partial superficial parotidectomy, superficial parotidectomy, and total parotidectomy dissect the facial nerve with a 1- to 2-cm margin of normal parotid parenchyma, removal of all parotid parenchyma lateral to the facial nerve, and removal of all parotid parenchyma, respectively. Extended parotidectomy can include sacrifice of the facial nerve and/or resection of adjacent structures.
ETIOLOGY Microscopic histological studies indicate that PA is characterized by focal absence of a capsule.1 The pseudocapsule, delicate and incomplete, allows pseudopodia (Fig. 1), satellite nodules, capsule infiltration, and tumor herniation to occur.2–5 The first hypothesis for RPA put forward by Patey in the 1950s4 noted the microscopically visible small lobulations or pseudopodia of tumor outside the presumed capsule, that during uncontrolled enucleation can potentially be detached and left within the residual normal salivary gland tissue.2 The second hypothesis is straightforward “tumor spill,” meaning that if the tumor is violated, PA cells may be seeded in Witt et al.: Management of Recurrent Pleomorphic Adenoma
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Other factors resulting in recurrence include incisional biopsy for suspected lymph nodes or cysts, a peroral approach to parapharyngeal tumors,15 and seeding by core needle or open biopsies. Rare multicentric primary tumor has been reported12; Batsakis reported a 0.5% incidence of multicentric tumor.26 Biological and genetic factors have been considered as causes of recurrence.27
IMAGING OF RECURRENCE
Fig. 1. Pseudopodia in primary pleomorphic adenoma (hematoxylin & eosin, 0.53). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
the operative wound and multiple new tumors may slowly start to grow in the surgical field. This is supported by RPA with multiple nodules following the surgical scar (Fig. 2) and a reportedly small (5%) but significant increase in recurrence with tumor spillage.6 In most cases, it is more accurate to use the term residual disease rather than recurrence, as most patients have never been free of disease.7 Others refute tumor spill and pseudopodia as causal mechanisms based on few observed recurrences after spill.8–11 Copious irrigation of the surgical bed has been advocated for tumor rupture and spill, although no study has proven the efficacy of this. The majority of RPAs are reported to result from preceding enucleation procedures.6,12–15 Historically, the high recurrence rate after enucleation led to a change in treatment.4,16,17 Enucleation was replaced by superficial parotidectomy for tumors in the superficial lobe. PA has a low rate of recurrence (1%–4%) with superficial parotidectomy and potentially even lower rate (0%–0.4%) with total parotidectomy.18 Enucleation results in recurrence rates as high as 45%.8,19–21 Pure en bloc excision is unlikely when the PA abuts the facial nerve, and therefore partial extracapsular dissection is the reality in most cases,6,22 thus explaining the possibility of recurrence even after superficial parotidectomy.16 The mean age at initial presentation of PA among patients who later developed recurrence is significantly lower (33–35 years of age) than the mean age for those who remain free of disease on long-term follow-up (45– 50 years of age).7,13,23,24 Not all studies support age as a factor in recurrence.18 Female gender is also a reported risk factor7,15,16 but again not in all studies.25 RPAs are said to occur more frequently with tumors that are hypocellular and chondromyxoid in nature, where there are higher rates of incomplete encapsulation,2 pseudopodia, and satellite nodules than with hypercellular subtypes.20 Other recent studies have suggested instead a higher rate of RPA with hypercellular tumors.12,23 Laryngoscope 00: Month 2014
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Delineation of the extent of the RPA is best depicted by magnetic resonance imaging (MRI), which demonstrates the multinodular nature of the disease and potential deep-lobe (Fig. 3) or parapharyngeal extension (Fig. 4). MRI can help in determining the amount of residual parotid gland. RPA lesions are usually round and of low intensity on T1-weighted MRI and of high intensity on T2-weighted MRI. With contrast administration, the lesions show mild enhancement. However, MRI can also be inadequate for identifying all nodules, and frequently the surgeon’s loupe magnification or the pathologist’s microscope reveals many more nodules than suspected from clinical assessment.3 When a patient presents with RPA, the number of nodules is probably much higher than is clinically evident or even detectable by MRI.
SURGICAL/HISTOPATHOLOGICAL PRESENTATION RPA occurs a mean of 7 to 10 years after initial surgery.11,14,28 Time intervals between operation and
Fig. 2. Magnetic resonance imaging in the sagittal plane, turbo spin-echo T1-weighted sequence. Multiple nodules are distributed as a string of beads between the residual parotid gland and the sternocleidomastoid muscle. The nodules extend from the floor of the external auditory canal, cranially, to the upper neck, caudally.
Witt et al.: Management of Recurrent Pleomorphic Adenoma
Fig. 3. Magnetic resonance imaging in the coronal plane, turbo spin-echo T2-weighted sequence. The left parotid region is occupied by a multinodular mass composed by lesions of different size, some of them without hyperintensity. Several nodules surround the sternocleidomastoid muscle, and some laterally displace the auricle.
undergone electromyography, and demonstrated that IFNM could reduce operative time, decrease the incidence rate of permanent facial nerve paralysis, and shorten the recovery time of postoperative facial nerve function.37 Liu et al. reported the percent of permanent facial paralysis in monitored patients who underwent total parotidectomy for RPA as 10.7%, compared with 23.3% in the unmonitored group.38 Although this difference was not significant, they significantly shortened the duration of surgery, significantly reduced the severity of facial nerve injury, and significantly shortened the recovery period of facial nerve paralysis. In RPA surgery, unlike primary surgery, the surgeon does not always skeletonize nerve branches, but instead attempts to preserve the fibrosis that surrounds the branches, which limits nerve exposure and mechanical manipulation. By avoiding devascularization and perineurium exposure, the surgeon can remove the RPA after identification of the nerve branches via nerve monitoring without exposing the nerve. This strategy potentially reduces surgical trauma caused by mechanical separation.
TREATMENT AND OUTCOME 12
recurrence are significantly shorter for enucleation. Thirty-three percent to 98% of RPAs are multifocal.2,23,29,30 Microscopically, many recurrences consist of up to 100 nodules or more. Most nodules are smaller than 1 mm. This explains the high incidence of second recurrences. Wittekindt et al. reported that the mean number of nodules was 26, and the maximal number was 266. 7 Multiple recurrences were found in 56 patients (52%), with a median follow-up of 20 years since the primary operation.7 Ultimately, 75% with a second recurrence in this cohort were treated with surgery only.
FACIAL NERVE OUTCOME NEUROMONITORING
IN
RPA
AND
Incidence rates of postoperative facial paralysis after primary parotid surgery are reported to be 9.1% to 64.0% for temporary facial paralysis and 0% to 3.9% for permanent facial paralysis.31,32 The incidence rates of temporary and permanent facial nerve dysfunction are considerably higher after RPA parotid surgery and are reported to be 90% to 100% and 11.3% to 40.0%, respectively.7,23,24,29,33 Rates of facial nerve dysfunction increase with each revision procedure.13,24,34 Previous dissection makes it difficult to distinguish the facial nerve from scar tissue. Retrograde facial nerve dissection—starting from the more likely undisturbed temporal facial nerve branch—has an important potential role in recurrent lesions. Another concern following tumor recurrence relates to the facial nerve that can be more closely adherent to tumor.35 Sacrifice of the facial nerve with microsurgical nerve grafting is reported to occur in 14% to 30% of cases in patients with RPA.30,36 Intraoperative facial nerve monitoring (IFNM) is a technique that has been used in parotid surgery. Makeieff et al. conducted a study of 32 RPA patients who had Laryngoscope 00: Month 2014
The surgical treatment of RPA is a challenge and has never been standardized. Observation is recommended for the elderly or medically infirm or in selected case waiting for a small lesion to grow.
Fig. 4. Magnetic resonance imaging in the coronal plane, turbo spin-echo T2-weighted sequence with fat saturation. Recurrent pleomorphic adenoma in a patient who underwent transoral removal as a primary treatment. Hyperintense nodules of variable size are disseminated along the left parapharyngeal space. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
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partmental resection superficial to the platysma and including the fat tissue, potentially harboring microlesions, can minimize the chance of recurrence. Ultimate control rates for first redo surgery alone are reported ranging from 36% to 98%.7,12,15,24,25,30,42 Patey, in the 1940s, showed enucleation followed by radium needle implant had superior control rates to enucleation.21 Today one may consider RT for microscopic rests of this benign disease (see Radiotherapy below); gross residual disease is unlikely to be cured by RT.42
OUTCOME OF SUBSEQUENT RECURRENCE OF THE RPA
Fig. 5. Magnetic resonance imaging in the coronal plane, turbo spin-echo T2-weighted sequence with fat saturation. Hyperintense nodules involving the upper neck are well evident.
Recurrences after enucleation, extracapsular dissection, or partial superficial parotidectomy can be treated by superficial parotidectomy or total parotidectomy depending on the location of the recurrence and where the facial nerve has not been dissected. A single superficial recurrent lesion after enucleation or limited superficial parotidectomy does not necessarily require total parotidectomy. It is recommended to resect the scar from the previous incision. Localized resection of the tumor has been employed after multiple recurrences or after previous total parotidectomy when it is the only option to preserve the facial nerve.28 Higher failure rates with re-excisional biopsy than with formal parotidectomy for RPA have been reported,39 but others have refuted this.24,40 Many authors recommend that uninodular or multinodular recurrence after superficial parotidectomy be treated by total parotidectomy because of unexpected multinodularity.3,15,20,25,36 Total parotidectomy may reduce, but does not prevent, leaving microscopic residuals. Rerecurrence rate after 15 years is reported as 75% with extended parotidectomy not followed by radiotherapy (RT).7 Radical and extended parotidectomies have been considered for patients with infiltration of branches or the main trunk of the facial nerve. The need of having to sacrifice a branch of the facial nerve during surgery for RPA is reported in 14% to 30% of patients.30,36 Facial nerve resection may be necessary for patients with a history of multiple recurrences or failed RT. Even total parotidectomy with facial nerve sacrifice does not prevent a further recurrence in all patients.41 When multinodular recurrences are involving subcutaneous tissues of the upper neck (Fig. 5), only a comLaryngoscope 00: Month 2014
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The recurrence rate for patients who were operated on for a second recurrence has been reported as 43% to 45% for patients with a 10-year follow-up.23,24 Recurrence rates are higher for previously recurrent tumors than for those after the first operation.20,40 The mean interval between the first recurrence and second recurrence is 9 years.23 Glas et al. analyzed 52 patients with RPA, treated after one or more recurrences; no significant influence was seen in the recurrence rate with respect to gender, age at initial treatment, time of first recurrence, and intraoperative tumor spillage.29 Wittekindt et al., in a group of 108 patients, observed a significantly higher rate of subsequent recurrences in female and younger patients, and in patients treated with a simple enucleation.7 Carew et al. analyzed 31 patients treated for RPA, and concluded that the extent of the first parotid operation was the only factor with a statistically significant impact on tumor control after resection of the recurrence.14 Local control was achieved in all patients whose initial procedures involved local excision.14 Enucleation is the cause of RPA in 55% to 75% of cases.3,11 Wittekindt et al. reported a recurrence rate increasing from 42% at 5 years to 75% at 15 years.7 Redaelli de Zinis et al. observed a prevalence of RPA at 33.3%, with an estimation of recurrence rate increasing from 14.1% at 5 years to 31.4% at 10 years, 43.0% at 15 years, and 57.2% at 20 years.30 In this series, predictors of recurrence were local excision instead of formal parotidectomy and presence of multinodular disease.30 Others also report a higher rate of re-recurrence after surgery for recurrence on patients who were treated initially with enucleation.23
PARAPHARYNGEAL SPACE RPA The risk of first recurrence is lower, but once a first recurrence is observed, the chance of curative treatment is lower and the risk of second recurrence for this location is reported as higher.25 PA of the parapharyngeal space tumors can rarely be excised with a complete cuff of normal tissue. In selected cases, osteotomies are needed to ensure access for tumor clearance.43–45 Paramedian osteotomy between the canine and first premolar and double mandibular osteotomies using a combination of a horizontal osteotomy above the lingual, and a paramedian osteotomy between the canine and first premolar Witt et al.: Management of Recurrent Pleomorphic Adenoma
TABLE I. Local Control After Radiation Therapy. S 1 RT
S Alone
Liu et al.34
13/16 (82%)
1/17 (6%)
Renehan et al.13 Dawson48
47/51 (92%) 18/20 (90%)
48/63 (76%) —
Samson et al.42
16/17 (96%)*
—
Carew et al.14 Chen et al.49
11/11 (100%) 32/34 (94%)†
14/20 (71%) —
Wallace et al.
50
Total
13/16 (75%)*
—
150/165 (91%)
63/100 (63%)
Follow-up Period
Median 12.5 years Minimum 48 months Not available Minimum 48 months Median 88 months Median 17.4 years Minimum 24 months
*Data are for microscopic residual disease only; patients receiving S 1 RT for macroscopic residual disease had a much lower control rate (1/4, 25% for Samson et al.; 5/9, 56% for Wallace et al.). † One patient developed a malignancy about 14 years after completion of RT. RT 5radiation therapy; S 5 surgery.
provide excellent surgical access.46 Transoral robotic surgery resulted in a 7/29 (24%) rate of capsule violation or tumor fragmentation in primary PA cases.47 In parapharyngeal multinodular recurrences after transoral resection, oropharyngeal mucosa should be included in the resection.
RADIOTHERAPY RT after surgery is not necessarily indicated for an isolated recurrence in a younger patient. Adjuvant radiation can be considered when complete extirpation of the recurrent disease is not possible, when sacrifice of the facial nerve would otherwise have been necessary, in cases of multinodular recurrence, or after multiple recurrences. A large tumor load is not likely to be cured with RT.42 Liu et al. achieved local control in 13 of 16 patients (82% at 10 years) with RPA treated with surgery and immediate postoperative radiation therapy (median dose 45 Gy). Local control with surgery alone was achieved in 1 out of 17 patients.34 Renehan et al. studied 114 patients with first recurrence RPA and reported significantly better, recurrence-free survival if patients were treated with postoperative RT (second recurrence in 8% in the postoperative RT group vs 24% in the surgery only group), and this effect was even more pronounced for multinodular RPA (4% second recurrence if treated with postoperative RT as opposed to 43% if treated by surgery alone).13 The second recurrence rate was limited to 10%, with the combination of surgery and RT in the series by Dawson48 and 4% in the Boston series by Samson et al.42 Carew et al. found 100% local control in patients treated for RPA with surgery and radiation, as opposed to a 71% local control in surgery-only patients, a trend that did not reach statistical significance.14 More recently, in a series of 34 patients treated with surgery followed by RT by Chen et al., after the first to sixth recurrence to a median dose of 50 Gy, a 20-year actuarial local control rate of 94% was reported.49 Wallace et al. report local control after combined treatment in 13 (75%) of 16 patients with subclinical disease and five (56%) of nine patients with gross disease.50 Laryngoscope 00: Month 2014
Douglas et al. reported their experience of fast neutron RT and recommended RT for selected cases when complete extirpation is not possible, when sacrifice of the facial nerve is necessary, or after multiple recurrences.51 To date, this technique, however, is not widely applied because of the severe late toxicity associated with it. Yugueros et al. followed 39 patients with RPA28; they found no significant difference in tumor control in relation to gender, time after the previous treatment, size of the tumor, type of resection, and postoperative RT. No prospective study exists to date that compares surgery versus RT alone or surgery combined with RT for RPA, and thus it remains difficult to justify radiating in an attempt to prevent recurrence of a benign tumor in many young patients. However, because RT has been reported in several series (Table I) to improve local control in patients with multinodular recurrence or multiple recurrences, adjuvant RT might be appropriate in selected patients when further recurrence is likely to result in significant damage to the facial nerve.13,14,34,42,48,49
CARCINOMA EX-PLEOMORPHIC ADENOMA The de novo malignant transformation of RPA is reported in 0% to 23% of cases.7,12,23,24,48 Others report no cases of malignant degeneration for RPA,15 including one series of 108 consecutive RPAs.7 The risk of malignant transformation may increase with time and with the number of recurrences and may be preceded by PA with severe dysplastic change.
CONCLUSION The most important cause of recurrence is enucleation with rupture and incomplete tumor excision at operation. Incomplete pseudocapsule, extracapsular extension, pseudopods of PA tissue and satellite PA beyond the pseudocapsule are also likely linked to RPA. Most RPAs are multinodular. MRI is the imaging study of choice for RPA. Nerve integrity monitoring may Witt et al.: Management of Recurrent Pleomorphic Adenoma
5
reduce morbidity for RPA. Treatment of RPA must be individualized. Total parotidectomy, given the multicentricity of RPA, is appropriate in many patients, but may be inadequate to control RPA. There is accumulating evidence from retrospective series that postoperative RT results in significantly better local control. A disturbing percentage of RPAs are incurable. All patients should be informed about the possibility of needing multiple treatment procedures for RPA.
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Witt et al.: Management of Recurrent Pleomorphic Adenoma
Rhinological and Otological Society, Inc.
Contemporary Review
Etiology and Management of Recurrent Parotid Pleomorphic Adenoma Robert Lee Witt, MD; David W. Eisele, MD; Randall P. Morton, MB, BS, MSc, FRACS; Piero Nicolai, MD; Vincent Vander Poorten, MD, PhD, MSc; Peter Zb€ aren, MD The objective of this review study was to encompass the relevant literature and current best practice options for this challenging, sometimes incurable problem. The source of the data was Ovid MEDLINE from 1946 to 2014. Review methods consisted of articles with clinical correlates. The most important cause of recurrence is enucleation with rupture and incomplete tumor excision at operation. Incomplete pseudocapsule, extracapsular extension, pseudopods of pleomorphic adenoma tissue, and satellite pleomorphic beyond the pseudocapsule are also likely linked to recurrent pleomorphic adenoma. Most recurrent pleomorphic adenoma are multinodular. Magnetic resonance imaging is the imaging study of choice for recurrent pleomorphic adenoma. Nerve integrity monitoring may reduce morbidity for recurrent pleomorphic adenoma. Treatment of recurrent pleomorphic adenoma must be individualized. Total parotidectomy, given the multicentricity of recurrent pleomorphic adenoma, is appropriate in many patients, but may be inadequate to control recurrent pleomorphic. There is accumulating evidence from retrospective series that postoperative radiation therapy results in significantly better local control. Key Words: pleomorphic adenoma, benign mixed tumor, recurrence, management, etiology. Level of Evidence: NA Laryngoscope, 00:000–000, 2014
INTRODUCTION Recurrence rates for pleomorphic adenoma (PA) are difficult to evaluate because of the small number of patients in most centers and the variability of follow-up. The predisposing factors for and management of recurrent pleomorphic adenoma (RPA) are varied. This contemporary review will encompass the relevant literature and current best practice options for this challenging, sometimes incurable problem.
METHODS An Ovid MEDLINE search was performed from January 1946 to April 2014 to identify English-language articles pub-
From the Department of Otolaryngology–Head & Neck Surgery (R.L.W.), Christiana Care/Thomas Jefferson University, Newark, Delaware, U.S.A.; Department of Otolaryngology–Head & Neck Surgery (D.W.E.), Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.; Department of Surgery (R.P.M.), University of Auckland; Department of Otolaryngology–Head & Neck Surgery (R.P.M.), CountiesManukau Health, University of Auckland, Auckland, New Zealand; Department of Otorhinolaryngology–Head and Neck Surgery (P.N.), University of Brescia, Brescia, Italy; Department of Otorhinolaryngology– Head and Neck Surgery (V.V.P.) and Department of Oncology (V.V.P.), Section Head & Neck Oncology, University Hospitals Leuven, Leuven, Belgium; Department of Otorhinolaryngology–Head and Neck Surgery (P.Z.), University Hospital Bern, Bern, Switzerland. Editor’s Note: This Manuscript was accepted for publication September 15, 2014. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Robert L. Witt, MD, 4745 OgletownStanton Rd, MAP #1, Suite 112, Newark, DE 19713. E-mail [email protected] DOI: 10.1002/lary.24964
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lished about RPA. A combination of relevant Medical Subject Headings, keywords, and limits were used in the search strategies. To broaden the abstract search, using keyword variation of parotid and recurrent, inclusion was not limited to etiology and management. To narrow the articles reviewed, abstracts were excluded if not pertaining to RPA. Various methods of parotidectomy are described in the literature, often interchangeably. Enucleation and extracapsular dissection do not dissect the facial nerve. Enucleation violates the capsule, whereas extracapsular dissection does not. Partial superficial parotidectomy, superficial parotidectomy, and total parotidectomy dissect the facial nerve with a 1- to 2-cm margin of normal parotid parenchyma, removal of all parotid parenchyma lateral to the facial nerve, and removal of all parotid parenchyma, respectively. Extended parotidectomy can include sacrifice of the facial nerve and/or resection of adjacent structures.
ETIOLOGY Microscopic histological studies indicate that PA is characterized by focal absence of a capsule.1 The pseudocapsule, delicate and incomplete, allows pseudopodia (Fig. 1), satellite nodules, capsule infiltration, and tumor herniation to occur.2–5 The first hypothesis for RPA put forward by Patey in the 1950s4 noted the microscopically visible small lobulations or pseudopodia of tumor outside the presumed capsule, that during uncontrolled enucleation can potentially be detached and left within the residual normal salivary gland tissue.2 The second hypothesis is straightforward “tumor spill,” meaning that if the tumor is violated, PA cells may be seeded in Witt et al.: Management of Recurrent Pleomorphic Adenoma
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Other factors resulting in recurrence include incisional biopsy for suspected lymph nodes or cysts, a peroral approach to parapharyngeal tumors,15 and seeding by core needle or open biopsies. Rare multicentric primary tumor has been reported12; Batsakis reported a 0.5% incidence of multicentric tumor.26 Biological and genetic factors have been considered as causes of recurrence.27
IMAGING OF RECURRENCE
Fig. 1. Pseudopodia in primary pleomorphic adenoma (hematoxylin & eosin, 0.53). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
the operative wound and multiple new tumors may slowly start to grow in the surgical field. This is supported by RPA with multiple nodules following the surgical scar (Fig. 2) and a reportedly small (5%) but significant increase in recurrence with tumor spillage.6 In most cases, it is more accurate to use the term residual disease rather than recurrence, as most patients have never been free of disease.7 Others refute tumor spill and pseudopodia as causal mechanisms based on few observed recurrences after spill.8–11 Copious irrigation of the surgical bed has been advocated for tumor rupture and spill, although no study has proven the efficacy of this. The majority of RPAs are reported to result from preceding enucleation procedures.6,12–15 Historically, the high recurrence rate after enucleation led to a change in treatment.4,16,17 Enucleation was replaced by superficial parotidectomy for tumors in the superficial lobe. PA has a low rate of recurrence (1%–4%) with superficial parotidectomy and potentially even lower rate (0%–0.4%) with total parotidectomy.18 Enucleation results in recurrence rates as high as 45%.8,19–21 Pure en bloc excision is unlikely when the PA abuts the facial nerve, and therefore partial extracapsular dissection is the reality in most cases,6,22 thus explaining the possibility of recurrence even after superficial parotidectomy.16 The mean age at initial presentation of PA among patients who later developed recurrence is significantly lower (33–35 years of age) than the mean age for those who remain free of disease on long-term follow-up (45– 50 years of age).7,13,23,24 Not all studies support age as a factor in recurrence.18 Female gender is also a reported risk factor7,15,16 but again not in all studies.25 RPAs are said to occur more frequently with tumors that are hypocellular and chondromyxoid in nature, where there are higher rates of incomplete encapsulation,2 pseudopodia, and satellite nodules than with hypercellular subtypes.20 Other recent studies have suggested instead a higher rate of RPA with hypercellular tumors.12,23 Laryngoscope 00: Month 2014
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Delineation of the extent of the RPA is best depicted by magnetic resonance imaging (MRI), which demonstrates the multinodular nature of the disease and potential deep-lobe (Fig. 3) or parapharyngeal extension (Fig. 4). MRI can help in determining the amount of residual parotid gland. RPA lesions are usually round and of low intensity on T1-weighted MRI and of high intensity on T2-weighted MRI. With contrast administration, the lesions show mild enhancement. However, MRI can also be inadequate for identifying all nodules, and frequently the surgeon’s loupe magnification or the pathologist’s microscope reveals many more nodules than suspected from clinical assessment.3 When a patient presents with RPA, the number of nodules is probably much higher than is clinically evident or even detectable by MRI.
SURGICAL/HISTOPATHOLOGICAL PRESENTATION RPA occurs a mean of 7 to 10 years after initial surgery.11,14,28 Time intervals between operation and
Fig. 2. Magnetic resonance imaging in the sagittal plane, turbo spin-echo T1-weighted sequence. Multiple nodules are distributed as a string of beads between the residual parotid gland and the sternocleidomastoid muscle. The nodules extend from the floor of the external auditory canal, cranially, to the upper neck, caudally.
Witt et al.: Management of Recurrent Pleomorphic Adenoma
Fig. 3. Magnetic resonance imaging in the coronal plane, turbo spin-echo T2-weighted sequence. The left parotid region is occupied by a multinodular mass composed by lesions of different size, some of them without hyperintensity. Several nodules surround the sternocleidomastoid muscle, and some laterally displace the auricle.
undergone electromyography, and demonstrated that IFNM could reduce operative time, decrease the incidence rate of permanent facial nerve paralysis, and shorten the recovery time of postoperative facial nerve function.37 Liu et al. reported the percent of permanent facial paralysis in monitored patients who underwent total parotidectomy for RPA as 10.7%, compared with 23.3% in the unmonitored group.38 Although this difference was not significant, they significantly shortened the duration of surgery, significantly reduced the severity of facial nerve injury, and significantly shortened the recovery period of facial nerve paralysis. In RPA surgery, unlike primary surgery, the surgeon does not always skeletonize nerve branches, but instead attempts to preserve the fibrosis that surrounds the branches, which limits nerve exposure and mechanical manipulation. By avoiding devascularization and perineurium exposure, the surgeon can remove the RPA after identification of the nerve branches via nerve monitoring without exposing the nerve. This strategy potentially reduces surgical trauma caused by mechanical separation.
TREATMENT AND OUTCOME 12
recurrence are significantly shorter for enucleation. Thirty-three percent to 98% of RPAs are multifocal.2,23,29,30 Microscopically, many recurrences consist of up to 100 nodules or more. Most nodules are smaller than 1 mm. This explains the high incidence of second recurrences. Wittekindt et al. reported that the mean number of nodules was 26, and the maximal number was 266. 7 Multiple recurrences were found in 56 patients (52%), with a median follow-up of 20 years since the primary operation.7 Ultimately, 75% with a second recurrence in this cohort were treated with surgery only.
FACIAL NERVE OUTCOME NEUROMONITORING
IN
RPA
AND
Incidence rates of postoperative facial paralysis after primary parotid surgery are reported to be 9.1% to 64.0% for temporary facial paralysis and 0% to 3.9% for permanent facial paralysis.31,32 The incidence rates of temporary and permanent facial nerve dysfunction are considerably higher after RPA parotid surgery and are reported to be 90% to 100% and 11.3% to 40.0%, respectively.7,23,24,29,33 Rates of facial nerve dysfunction increase with each revision procedure.13,24,34 Previous dissection makes it difficult to distinguish the facial nerve from scar tissue. Retrograde facial nerve dissection—starting from the more likely undisturbed temporal facial nerve branch—has an important potential role in recurrent lesions. Another concern following tumor recurrence relates to the facial nerve that can be more closely adherent to tumor.35 Sacrifice of the facial nerve with microsurgical nerve grafting is reported to occur in 14% to 30% of cases in patients with RPA.30,36 Intraoperative facial nerve monitoring (IFNM) is a technique that has been used in parotid surgery. Makeieff et al. conducted a study of 32 RPA patients who had Laryngoscope 00: Month 2014
The surgical treatment of RPA is a challenge and has never been standardized. Observation is recommended for the elderly or medically infirm or in selected case waiting for a small lesion to grow.
Fig. 4. Magnetic resonance imaging in the coronal plane, turbo spin-echo T2-weighted sequence with fat saturation. Recurrent pleomorphic adenoma in a patient who underwent transoral removal as a primary treatment. Hyperintense nodules of variable size are disseminated along the left parapharyngeal space. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
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partmental resection superficial to the platysma and including the fat tissue, potentially harboring microlesions, can minimize the chance of recurrence. Ultimate control rates for first redo surgery alone are reported ranging from 36% to 98%.7,12,15,24,25,30,42 Patey, in the 1940s, showed enucleation followed by radium needle implant had superior control rates to enucleation.21 Today one may consider RT for microscopic rests of this benign disease (see Radiotherapy below); gross residual disease is unlikely to be cured by RT.42
OUTCOME OF SUBSEQUENT RECURRENCE OF THE RPA
Fig. 5. Magnetic resonance imaging in the coronal plane, turbo spin-echo T2-weighted sequence with fat saturation. Hyperintense nodules involving the upper neck are well evident.
Recurrences after enucleation, extracapsular dissection, or partial superficial parotidectomy can be treated by superficial parotidectomy or total parotidectomy depending on the location of the recurrence and where the facial nerve has not been dissected. A single superficial recurrent lesion after enucleation or limited superficial parotidectomy does not necessarily require total parotidectomy. It is recommended to resect the scar from the previous incision. Localized resection of the tumor has been employed after multiple recurrences or after previous total parotidectomy when it is the only option to preserve the facial nerve.28 Higher failure rates with re-excisional biopsy than with formal parotidectomy for RPA have been reported,39 but others have refuted this.24,40 Many authors recommend that uninodular or multinodular recurrence after superficial parotidectomy be treated by total parotidectomy because of unexpected multinodularity.3,15,20,25,36 Total parotidectomy may reduce, but does not prevent, leaving microscopic residuals. Rerecurrence rate after 15 years is reported as 75% with extended parotidectomy not followed by radiotherapy (RT).7 Radical and extended parotidectomies have been considered for patients with infiltration of branches or the main trunk of the facial nerve. The need of having to sacrifice a branch of the facial nerve during surgery for RPA is reported in 14% to 30% of patients.30,36 Facial nerve resection may be necessary for patients with a history of multiple recurrences or failed RT. Even total parotidectomy with facial nerve sacrifice does not prevent a further recurrence in all patients.41 When multinodular recurrences are involving subcutaneous tissues of the upper neck (Fig. 5), only a comLaryngoscope 00: Month 2014
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The recurrence rate for patients who were operated on for a second recurrence has been reported as 43% to 45% for patients with a 10-year follow-up.23,24 Recurrence rates are higher for previously recurrent tumors than for those after the first operation.20,40 The mean interval between the first recurrence and second recurrence is 9 years.23 Glas et al. analyzed 52 patients with RPA, treated after one or more recurrences; no significant influence was seen in the recurrence rate with respect to gender, age at initial treatment, time of first recurrence, and intraoperative tumor spillage.29 Wittekindt et al., in a group of 108 patients, observed a significantly higher rate of subsequent recurrences in female and younger patients, and in patients treated with a simple enucleation.7 Carew et al. analyzed 31 patients treated for RPA, and concluded that the extent of the first parotid operation was the only factor with a statistically significant impact on tumor control after resection of the recurrence.14 Local control was achieved in all patients whose initial procedures involved local excision.14 Enucleation is the cause of RPA in 55% to 75% of cases.3,11 Wittekindt et al. reported a recurrence rate increasing from 42% at 5 years to 75% at 15 years.7 Redaelli de Zinis et al. observed a prevalence of RPA at 33.3%, with an estimation of recurrence rate increasing from 14.1% at 5 years to 31.4% at 10 years, 43.0% at 15 years, and 57.2% at 20 years.30 In this series, predictors of recurrence were local excision instead of formal parotidectomy and presence of multinodular disease.30 Others also report a higher rate of re-recurrence after surgery for recurrence on patients who were treated initially with enucleation.23
PARAPHARYNGEAL SPACE RPA The risk of first recurrence is lower, but once a first recurrence is observed, the chance of curative treatment is lower and the risk of second recurrence for this location is reported as higher.25 PA of the parapharyngeal space tumors can rarely be excised with a complete cuff of normal tissue. In selected cases, osteotomies are needed to ensure access for tumor clearance.43–45 Paramedian osteotomy between the canine and first premolar and double mandibular osteotomies using a combination of a horizontal osteotomy above the lingual, and a paramedian osteotomy between the canine and first premolar Witt et al.: Management of Recurrent Pleomorphic Adenoma
TABLE I. Local Control After Radiation Therapy. S 1 RT
S Alone
Liu et al.34
13/16 (82%)
1/17 (6%)
Renehan et al.13 Dawson48
47/51 (92%) 18/20 (90%)
48/63 (76%) —
Samson et al.42
16/17 (96%)*
—
Carew et al.14 Chen et al.49
11/11 (100%) 32/34 (94%)†
14/20 (71%) —
Wallace et al.
50
Total
13/16 (75%)*
—
150/165 (91%)
63/100 (63%)
Follow-up Period
Median 12.5 years Minimum 48 months Not available Minimum 48 months Median 88 months Median 17.4 years Minimum 24 months
*Data are for microscopic residual disease only; patients receiving S 1 RT for macroscopic residual disease had a much lower control rate (1/4, 25% for Samson et al.; 5/9, 56% for Wallace et al.). † One patient developed a malignancy about 14 years after completion of RT. RT 5radiation therapy; S 5 surgery.
provide excellent surgical access.46 Transoral robotic surgery resulted in a 7/29 (24%) rate of capsule violation or tumor fragmentation in primary PA cases.47 In parapharyngeal multinodular recurrences after transoral resection, oropharyngeal mucosa should be included in the resection.
RADIOTHERAPY RT after surgery is not necessarily indicated for an isolated recurrence in a younger patient. Adjuvant radiation can be considered when complete extirpation of the recurrent disease is not possible, when sacrifice of the facial nerve would otherwise have been necessary, in cases of multinodular recurrence, or after multiple recurrences. A large tumor load is not likely to be cured with RT.42 Liu et al. achieved local control in 13 of 16 patients (82% at 10 years) with RPA treated with surgery and immediate postoperative radiation therapy (median dose 45 Gy). Local control with surgery alone was achieved in 1 out of 17 patients.34 Renehan et al. studied 114 patients with first recurrence RPA and reported significantly better, recurrence-free survival if patients were treated with postoperative RT (second recurrence in 8% in the postoperative RT group vs 24% in the surgery only group), and this effect was even more pronounced for multinodular RPA (4% second recurrence if treated with postoperative RT as opposed to 43% if treated by surgery alone).13 The second recurrence rate was limited to 10%, with the combination of surgery and RT in the series by Dawson48 and 4% in the Boston series by Samson et al.42 Carew et al. found 100% local control in patients treated for RPA with surgery and radiation, as opposed to a 71% local control in surgery-only patients, a trend that did not reach statistical significance.14 More recently, in a series of 34 patients treated with surgery followed by RT by Chen et al., after the first to sixth recurrence to a median dose of 50 Gy, a 20-year actuarial local control rate of 94% was reported.49 Wallace et al. report local control after combined treatment in 13 (75%) of 16 patients with subclinical disease and five (56%) of nine patients with gross disease.50 Laryngoscope 00: Month 2014
Douglas et al. reported their experience of fast neutron RT and recommended RT for selected cases when complete extirpation is not possible, when sacrifice of the facial nerve is necessary, or after multiple recurrences.51 To date, this technique, however, is not widely applied because of the severe late toxicity associated with it. Yugueros et al. followed 39 patients with RPA28; they found no significant difference in tumor control in relation to gender, time after the previous treatment, size of the tumor, type of resection, and postoperative RT. No prospective study exists to date that compares surgery versus RT alone or surgery combined with RT for RPA, and thus it remains difficult to justify radiating in an attempt to prevent recurrence of a benign tumor in many young patients. However, because RT has been reported in several series (Table I) to improve local control in patients with multinodular recurrence or multiple recurrences, adjuvant RT might be appropriate in selected patients when further recurrence is likely to result in significant damage to the facial nerve.13,14,34,42,48,49
CARCINOMA EX-PLEOMORPHIC ADENOMA The de novo malignant transformation of RPA is reported in 0% to 23% of cases.7,12,23,24,48 Others report no cases of malignant degeneration for RPA,15 including one series of 108 consecutive RPAs.7 The risk of malignant transformation may increase with time and with the number of recurrences and may be preceded by PA with severe dysplastic change.
CONCLUSION The most important cause of recurrence is enucleation with rupture and incomplete tumor excision at operation. Incomplete pseudocapsule, extracapsular extension, pseudopods of PA tissue and satellite PA beyond the pseudocapsule are also likely linked to RPA. Most RPAs are multinodular. MRI is the imaging study of choice for RPA. Nerve integrity monitoring may Witt et al.: Management of Recurrent Pleomorphic Adenoma
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reduce morbidity for RPA. Treatment of RPA must be individualized. Total parotidectomy, given the multicentricity of RPA, is appropriate in many patients, but may be inadequate to control RPA. There is accumulating evidence from retrospective series that postoperative RT results in significantly better local control. A disturbing percentage of RPAs are incurable. All patients should be informed about the possibility of needing multiple treatment procedures for RPA.
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