Am J Otolaryngol xxx (xxxx) xxxx

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Am J Otolaryngol
journal homepage: www.elsevier.com/locate/amjoto

Carcinoma ex pleomorphic adenoma: A review of incidence, demographics,

risk factors, and survival☆,☆☆,☆☆☆
Avigeet Gupta , Sina Koochakzadeh, David M. Neskey, Shaun A. Nguyen, Eric J. Lentsch
⁎

Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA

ARTICLE INFO ABSTRACT

Keywords: Purpose: Identify variables that are independent predictors of survival in carcinoma ex pleomorphic adenoma
Carcinoma ex pleomorphic adenoma (CXPA) of the major salivary glands using a population-based database and evaluate the incidence and man-
Salivary malignancy agement strategies for this rare malignancy.
Parotid gland Materials and Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for all
Survival
cases of major salivary gland CXPA from 1973 to 2015.
Results: Of the 619 patients identified, the parotid gland was the most common site of involvement (76.9%, 476/
619). The reported incidence of CXPA has risen in the past decade (2005–2015, 0.24 to 0.63 per 1,000,000). The
2-year and 5-year disease-specific survival (DSS) rates were 90.3% and 80.4%, respectively. On univariate
analysis, facial nerve sacrifice was not a statistically significant predictor of survival (HR = 1.213, 95% CI
[0.588–2.058], P = 0.602). Patients with a tumor size > 4 cm, multiple positive lymph nodes, and distant
metastatic disease had a 2 to 4-fold statistically significant increase in mortality using a multivariate analysis.
Statistical significance was not demonstrated in the DSS of patients who underwent partial versus total par-
otidectomy procedures.
Conclusions: CXPA is a rare salivary malignancy that has a reported increased incidence in the last decade.
Tumor size > 4 cm, multiple positive lymph nodes, and distant metastatic disease are predictors of disease-
specific mortality. Further research should be conducted to improve early detection and survival strategies for
this salivary cancer.
Level of Evidence: 4.

1. Introduction should raise suspicion for CXPA. The gold standard for diagnosing
CXPA is with histopathological evaluation of the suspected lesion [6].
Carcinoma ex pleomorphic adenoma (CXPA) is a rare malignant Fine needle aspiration cytology is typically used for preoperative eva-
tumor of the salivary glands [1]. CXPA is part of the malignant mixed luation. Diagnosis can be challenging if the entire PA component is
tumors category, which contains both benign and malignant compo- replaced by the malignant tumor. On the other hand, the malignant
nents on histologic analysis. This malignant tumor arises from the component may be sparse or scattered and missed when analyzing the
epithelial component of either primary or recurrent pleomorphic ade- pathological specimen [1]. Both scenarios can lead to misdiagnosis. As
noma (PA) [1]. Based on prior studies, the average prevalence of CPXA a result, this high-grade tumor can potentially lead to distant metas-
ranges from approximately 3% to 15% among all malignant salivary tasis. In terms of prognosis, survival rates reported in previous litera-
tumors [2–5]. ture range from 30% to over 70% [1–4,7].
CXPA most commonly presents as a firm mass in the parotid gland, Currently, there is limited body of evidence regarding the man-
although the submandibular and minor salivary glands may also be agement of these malignant salivary tumors. The purpose of this study
involved [6]. This presentation can be mistaken for a PA; however, a is to provide a current and comprehensive update on the management
rapid increase in size observed in a previously slow growing mass of these rare tumors by querying the Surveillance, Epidemiology, and

☆
No disclosures, financial or otherwise.
☆☆
No conflicts of interest.
☆☆☆
No financial support.
⁎
Corresponding author at: 135 Rutledge Avenue, MSC 550, Charleston, SC 29425, USA.
E-mail address: [email protected] (A. Gupta).

https://doi.org/10.1016/j.amjoto.2019.102279
Received 17 July 2019
0196-0709/ © 2019 Elsevier Inc. All rights reserved.

Please cite this article as: Avigeet Gupta, et al., Am J Otolaryngol, https://doi.org/10.1016/j.amjoto.2019.102279
A. Gupta, et al. Am J Otolaryngol xxx (xxxx) xxxx

End Results (SEER) database for incidence, demographic factors,

treatment modalities, and determining predictors of survival in CXPA.

2. Materials and Methods

2.1. Data

Case-based data was obtained using the SEER database of the

National Cancer Institute (NCI). Through data from population-based
registries, around 34.6% of the population of the United States is in-
cluded in the SEER Program. These registries obtain pertinent data
regarding cancer, including but not limited to site, stage at diagnosis,
initial treatment and survival [8]. In this study, the SEER 18 Registry
Research Data (cases from 1973 to 2015, based on the November 2016 Fig. 1. Incidence of Carcinoma ex Pleomorphic Adenoma from 1973 to 2015 by
submission) was utilized with SEER*Stat Software Version 8.3.4 [9]. 5-Year Average Interval.
This study was deemed to be exempt from review by the Office of Re-
search Integrity of the Medical University of South Carolina. 3.2. Sociodemographic and tumor characteristics
Patients were included based on the following International
Classification of Diseases for Oncology, Third Editions codes: 8941/3: Demographic data and tumor characteristics of these patients are
Carcinoma in pleomorphic adenoma, C07.9, C08.0, C08.1, C08.8, C08.9 located in Table 1. The mean age of the entire cohort was 62.1 years (17
for major salivary glands occurring from 1973 to 2015. Demographic to 97). Most patients were identified to be male (55.9%, 346),
variables collected include age at diagnosis, sex, race, and ethnicity.
Disease characteristics include tumor location and size, tumor exten-
sion, lymph node involvement, and presence of metastasis. Overall Table 1
American Joint Commission on Cancer tumor stage was categorized to Carcinoma ex Pleomorphic Adenoma population characteristics.
be either early stage (I-II) or late stage (III-IV) dichotomous variables Characteristics Number of patients
for analysis. Tumor grade was also categorized into dichotomous
variables as either low grade (well-to-moderately differentiated) or N = 619a (SD) %a
high grade (poorly-to-undifferentiated/anaplastic) disease. The
Sex
American Head and Neck Society neck dissection guidelines were used Male 346 55.9
to classify lymph nodes into corresponding cervical neck levels [10]. Female 273 44.1
Treatment data included use of radiation or surgery. Surgically treated Mean age in years 62.1 (14.6)
patients were categorized into total vs partial parotidectomy. Types of Race
surgical procedures performed were ascertained by the SEER database Caucasian 449 72.5
coding classification of surgical procedures from 1998 to 2015. The African-American 61 9.9
Other 109 17.6
number of patients with preserved or sacrificed facial nerve was also
reported. Ethnicity
Non-Hispanic 574 92.7
Hispanic 45 7.3

2.2. Statistical analysis Tumor location

Parotid 476 76.9
Submandibular 110 17.8
Data analyses were performed with SPSS 24.0 (SPSS Inc., IBM Corp., Sublingual 1 0.2
Armonk, NY), SigmaPlot 12.5 (Systat Software, Inc., San Jose, CA), and Major Salivary Gland NOS 32 5.2
MedCalc 18.10.2 (Ostend, Belgium). Categorical variables were sum- Tumor size
marized by frequency and percentage. Continuous variables were ≤2 cm 132 25.3
summarized by mean ± standard deviation or median and inter- 2–4 cm 214 41.1
quartile range where appropriate. Two-year and Five-year Overall ≥4 cm 177 34.0
Mean tumor size 3.6 (2.4)
Survival (OS) and Disease Specific Survival (DSS) rates were calculated
using Kaplan-Meier estimates of survival. Univariate and multivariate Tumor extension
None 401 67.3
Cox proportional hazards regression analyses were performed to adjust
Extraparenchymal extension 195 32.7
for potential confounding variables. A Wald forward stepwise elim-
Lymph Nodes examined
ination method was used for the final multivariable model. A P value
Not examined 229 39.1
of < 0.05 was considered to indicate a statistically significant differ- One examined 62 10.6
ence for all statistical tests. Multiple examined 295 50.3
Mean no. of nodes examined 12.1 (22.2)

Positive lymph nodes

3. Results None 260 70.5
1 29 7.9
>1 80 21.7
3.1. Incidence
Distant metastases
None 378 94.5
The reported incidence of CXPA has been on the rise in the last
Distant metastases 22 5.5
decade (0.24 to 0.63 per 1,000,000 from 2005 to 2015), with an overall
percent change of 163%. During the period of 1973 to 2015, 619 pa- Abbreviations: SD, standard deviation; NOS, not otherwise specified.
tients were identified using the aforementioned database search criteria a
Total number of cases for certain variables may be less than N because of
(Fig. 1). missing values.

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Table 2
Carcinoma ex Pleomorphic Adenoma treatment modalities.
Treatment Number of Patients

N = 619a %

b
Surgery
No surgery 17 2.8
Surgery 600 97.2

Type of surgery
Partial parotidectomy 273 52.5
Total parotidectomy 213 42.3

Facial nerveb
Spared 181 68.8
Sacrificed 82 31.2

Radiation
None 240 38.7
External beam 379 61.2

Chemotherapy
None/Unknown 549 88.7
Chemotherapy 70 11.3

a
Total number of cases for certain variables may be less than N because of
missing values.
b
Surgery type and facial nerve were identified for patients from 1998 to Fig. 2. Partial versus Total Parotidectomy Kaplan-Meier Disease Specific
2015. Survival Comparison.

Caucasian (72.5%, 449), and Non-Hispanic (92.7%, 574). The parotid

gland was noted to be the most common site (76.9%, 476) of involve-
ment. Mean tumor size was noted to be 3.6 (2.4) cm, and extra-
parenchymal extension was observed in 32.7% (195) of patients. The
majority of patients had at least one node examined (60.9%, 357). The
mean number of nodes examined was 12.1 (22.2). Among cases with
reported data, 5.5% (22) had distant metastatic disease.

3.3. Management strategies

The primary method of treatment of this tumor was surgical re-

section (97.2%, 600). Among those that underwent parotid gland re-
section, 273 (52.5%) patients had partial parotidectomy and 42.3% had
total parotidectomy procedures. The facial nerve was sacrificed in
31.2% (82) of cases. Within the entire cohort of patients, the majority
(61.2%) received external beam radiation. Only a small minority
(11.3%) received chemotherapy. Table 2 provides data on the various
treatment modalities for CXPA patients.

3.4. Survival analyses

The overall 2-year and 5-year survival rates were noted to be 84.6%
and 68.5%, respectively. Overall rates of DSS at 2-year and 5-year in-
Fig. 3. Kaplan-Meier Disease Specific Survival Stratified by Tumor Size.
tervals were 90.3% and 80.4%, respectively. Survival analysis of those
who underwent partial or total parotidectomy demonstrated no sig-
nificant differences in survival using a log-rank test (P = 0.278) (HR = 5.313, 95% CI [2.424–11.647]), late stage tumors (HR = 5.678,
(Fig. 2). Stratification of DSS by tumor size demonstrated a decreased 95% CI [2.562–12.583]), and multiple lymph node involvement
DSS with an increased tumor size. There was a significant difference in (HR = 5.411, 95% CI [3.374–8.677]) were associated with a > 5-fold
survival among patients with tumors of 4 cm or greater and those with a increase in mortality. On the other hand, partial parotidectomy was
tumor size of < 4 cm using a log-rank test (P < 0.001) (Fig. 3). associated with decreased mortality (HR = 0.636, 95% CI
[0.413–0.979]). Of note, facial nerve sacrifice was not a demonstrated
to be a statistically significant predictor of survival (HR = 1.213, 95%
3.5. Predictors of survival
CI [0.588–2.058], P = 0.602).
After adjusting for relevant covariates using multivariable analysis,
The following tumor characteristics were demonstrated to be sta-
tumor size of 4 cm or greater (HR = 2.394, 95% CI [1.121–5.113]),
tistically significant (P < 0.05) predictors of mortality by univariate
multiple positive lymph nodes (HR = 3.886, 95% CI [1.806–8.364]),
analyses: high grade, late stage, distant metastasis, tumor size, extra-
and distant metastatic disease (HR = 3.661, 95% CI [1.352–9.915])
parenchymal extension, multiple lymph node involvement (lymph node
were found to be significant (P < 0.05) independent predictors of
levels I–V), and partial parotidectomy (Table 3). Notably, distant me-
mortality (Table 4).
tastasis was associated with a 13-fold increase in mortality (hazard ratio
(HR) = 12.984, 95% CI [6.926–24.338]). High grade tumors

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Table 3 noted to be 0.68 per 1,000,000 by Rebhun et al. [8] using population-
Univariate analyses of disease-specific survival. based data through 2011. Based upon our study, the reported incidence
Risk factor Hazard ratio 95% CI P value of CXPA has been rising, especially in the last decade (0.24 to 0.63 per
1,000,000 from 2005 to 2015). A possible interpretation of this result
Female 1.213 0.826–1.782 0.325 may arise from the increased recognition and awareness of CXPA as a
Age 1.012 0.998–1.026 0.086
specific diagnostic entity by pathologists that specialize in salivary
African-American 0.724 0.318–1.652 0.444
High grade 5.313 2.424–11.647 < 0.0001⁎
gland malignancies. The pathological diagnosis of CXPA can prove to be
Late stage 5.678 2.562–12.583 < 0.0001⁎ difficult in unusual cases and lead to potential misclassifications. Dif-
Distant metastasis 12.984 6.926–24.338 < 0.0001⁎ ferential diagnoses for CXPA include, but are not limited to, benign
Tumor size pleomorphic adenomas, metastatic mixed tumors, high grade salivary
≤2 cm 0.511 0.288–0.908 0.022⁎ adenocarcinomas, and other salivary gland malignancies.
2-4 cm 0.589 0.366–0.946 0.029⁎ The pathogenesis of this disease is poorly understood, but geo-
≥4 cm 2.642 1.714–4.073 < 0.0001⁎
graphical differences in the prevalence of this tumor have been pre-
Extraparenchymal Extension 3.677 2.423–5.579 < 0.0001⁎
viously described. In the United Kingdom, Malata et al. [9] demonstrated
Number of positive nodes
that CXPA represents 25% of all primary parotid malignancies. In con-
One 1.347 0.645–2.812 0.428
Multiple 5.411 3.374–8.677 < 0.0001⁎
trast, CXPA had a prevalence of 14% of primary parotid malignancies in
Switzerland [4], and only 10% in Japan [13]. In the United States, a
Lymph node level
Level 1 4.041 2.204–7.410 < 0.0001⁎
study by Byrne and Spector [14] noted CXPA to represent 12% of pri-
Level 2 4.707 4.707–7.648 < 0.0001⁎ mary parotid cancers. Further work is necessary to understand the
Level 3 6.785 3.984–11.555 < 0.0001⁎ burden of disease, risk factors of pathogenesis, geographical differences,
Level 4 5.463 2.365–12.618 < 0.0001⁎ and this phenomenon of a reported rising incidence in the United States.
Level 5 7.688 3.675–16.080 < 0.0001⁎

Surgery 4.3. Prognostic predictors of survival

Partial Parotidectomy 0.636 0.413–0.979 0.040⁎
Total Parotidectomy 1.035 0.666–1.606 0.879
Facial Nerve Sacrifice 1.213 0.588–2.503 0.602
The rates of 5-year survival of CXPA have been quite variable in the
Adjuvant Radiotherapy 1.361 0.900–2.058 0.144 previous literature, ranging from 25% to 75% [1,2,4,6,15]. Overall
survival at 5 years was 68.5% using Kaplan-Meier analysis in our study,
Abbreviation: CI, confidence interval. whereas 5-year DSS was demonstrated to be 80.4% using our reported
Referents: Male, Caucasian, low grade, early stage, no distant metastatic dis- data that represents the United States population. Our study suggests
ease, no extraparenchymal extension, node-negative disease, no surgery, facial that the DSS of CXPA of the SEER database is not as poor as previously
nerve sparing, no external beam radiation.
published reports. However, this result should be cautiously interpreted
⁎
Denoted values achieved significance with P < 0.05.
with the understanding of possible misclassifications of the tumor
pathologies as previously mentioned.
Table 4
Based on univariate regression analyses, patients with larger tumor
Multivariate analysis of disease-specific survival.
size (≥4 cm), high grade disease, late stage disease, extraparenchymal
Risk factor Hazard ratio 95% CI P value extension, multiple lymph node involvement, and distant metastatic
disease were found to have an increased Cox proportional HR for dis-
Tumor size ≥ 4 cm 2.394 1.121–5.113 0.024⁎
Multiple positive nodes 3.886 1.806–8.364 0.001⁎ ease specific mortality. These predictors of survival have been pre-
Distant metastasis 3.661 1.352–9.915 0.011⁎ viously reported in the literature, highlighting the need to focus upon
these risk factors for pursuing aggressive treatment [11].
Abbreviation: CI, confidence interval. Most commonly, lymphatic spread of parotid malignancies occurs
Referents: tumor size ≤2 cm, node-negative disease, no distant metastatic from intraparotid nodes to level I and II cervical nodes of the neck. Of
disease.
note, patients with cervical neck level involvement had a 2 to 5-fold
⁎
Denoted values achieved significance with P < 0.05.
increase risk of mortality as compared to patients without cervical
nodal involvement in our study. Elective surgical management of the
4. Discussion
cervical neck should be considered for high-grade CXPA based on a
large database study by Xiao et al. [16] of 22,653 patients with parotid
4.1. Importance
malignancies. However, there is no consensus statement from the
American Head and Neck Society regarding the role of elective neck
To the best of our knowledge, this study represents the largest the
dissection for occult nodal disease in parotid malignancies, but this
cohort of major salivary gland CXPA patients in the literature using a
warrants further investigation [16,17].
population-based database. Previous works on this topic have been
In our study, multivariate analysis revealed that patients with a
limited and have not provided a comprehensive analysis of the prog-
tumor size of 4 cm or greater, multiple positive nodal involvement, and
nostic factors and treatment modalities for this malignant salivary
distant metastatic disease had a 2 to 4-fold increase in the HR for dis-
gland tumor. Chen et al. [11] conducted a population-level analysis of
ease-specific mortality. These results are consistent with previous lit-
CXPA using the SEER database; however, their study included patients
erature demonstrating that patients with late stage disease have lower
from 1988 to 2009, had a smaller population size (278 patients), and
rates of 5-year survival [16].
was solely limited to the parotid gland. Other attempts to quantify the
burden of this disease have been conducted at an institutional level and
4.4. Treatment modalities
in case reports, highlighting the paucity of literature regarding the
management of this malignancy.
Although there is no well-established standard of care for this
tumor, surgical resection is the mainstay treatment. Our study de-
4.2. Incidence and prevalence monstrated that almost all patients with CXPA had some type of sur-
gical procedure performed (97%). Options for surgical resection of the
Malignant salivary gland tumors represent approximately 5% of parotid site include partial or superficial parotidectomy when the dis-
head and neck malignancies [12]. The previous incidence of CXPA was ease is superficial to the facial nerve. In more involved cases, facial

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