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Πέμπτη 20 Ιουνίου 2019

The Difference in the Clinical Features Between Carcinoma ex Pleomorphic Adenoma and Pleomorphic Adenoma
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Jungirl Seok, MD, Se Jin Hyun, MD, Woo-Jin Jeong, MD, PhD, ...
First Published June 13, 2019 Research Article 
https://doi.org/10.1177/0145561319855376
Article information
  Free Access
Abstract
Carcinoma ex pleomorphic adenoma (CXPA) arises from the primary or recurrent benign pleomorphic adenoma. The purpose of this study was to evaluate the clinical features that could be referenced in the differentiation. The medical records of 221 patients with pleomorphic adenoma and 15 patients with CXPA were retrospectively reviewed. Clinical characteristics, computed tomography and magnetic resonance imaging findings, and surgical pathology were analyzed. Patients with CXPA were older (55.1 vs 42.3; P < .01). Carcinoma ex pleomorphic adenoma was observed at higher rates in the minor salivary glands (24.9% vs 2.7%) and higher incidence of regional lymph node enlargement (P = .04). While all CXPA showed a low-to-intermediate mean apparent diffusion coefficient value (ADC), most of pleomorphic adenoma had an intermediate-to-high (P = .01). From this study, the following features should be considered as the clinical features of CXPA: (1) old age; (2) minor salivary gland tumor; (3) regional lymph node enlargement (>5 mm); and (4) low ADC findings.

Keywords carcinoma ex pleomorphic adenoma, pleomorphic adenoma, salivary gland tumor
Introduction
Pleomorphic adenoma is the most common salivary gland neoplasm, constituting up to 60% of all benign salivary gland tumors, regardless of major or minor tumors.1 The first-line diagnosis for patients visiting a clinic with lumps or swelling in the salivary gland is usually pleomorphic adenoma. Carcinoma ex pleomorphic adenoma (CXPA) is defined as a carcinoma arising from the primary (de novo) or recurrent benign pleomorphic adenoma,2 and it can be composed of various histologic subtypes, including high-grade salivary duct carcinoma, adenocarcinoma not otherwise specified, myoepithelial carcinoma, and sarcomatoid carcinoma, among others.3

Carcinoma ex pleomorphic adenoma may be asymptomatic2 and has similar clinical presentations as benign pleomorphic adenoma.4,5 In most cases, the diagnostic accuracy in salivary gland lesions is lower for malignant lesions than for benign lesions; thus, a type-specific diagnosis is more difficult.6 Sensitivity of preoperative needle biopsy is high but, there is always the possibility of missing malignant tumors.7,8 Therefore, to make a differential diagnosis, understanding the clinical features of CXPA is necessary by comparing with pleomorphic adenoma. This study aimed to compare the clinical features between the 2 diseases and examine which features could be referenced in the differentiation of the 2 diseases.

Patients and Methods
Ethical Considerations
The study protocol was reviewed and approved by the institutional review board of Seoul National University Bundang Hospital; a waiver of informed consent was granted due to the retrospective design of the study (IRB No. B-1812-508-104).

Patients
The medical records of 221 patients with pleomorphic adenoma and 15 patients with CXPA between January 2008 and December 2017 at a single tertiary hospital were retrospectively reviewed. The diagnosis was confirmed by the pathologic report after surgery. Patients’ age at the initial diagnosis, gender, clinical symptoms and signs, tumor location, radiologic images, and pathologic reports were reviewed. Eleven of the 221 pleomorphic adenoma cases were recurred cases and 2 of 15 CXPA cases were originally pleomorphic adenoma which had been left untreated.

Review of Radiologic Test Findings
From computed tomography (CT) scan, the information about tumor size (maximal diameter), involvement of deep lobe, multiplicity, boundary definition (well-defined vs ill-defined), lymphadenopathy (positive if > 5 mm), necrosis (ill-defined low attenuation), and cystic change (well-defined low attenuation) were reviewed.

From an magnetic resonance imaging (MRI) scan, the information about heterogeneity (homogenous vs heterogenous), T1, T2 signal intensity (low vs high), enhancement (unenhanced vs enhanced), mean apparent diffusion coefficient (ADC) value, and presence of extracapsular extension and lymphadenopathy (positive if > 5 mm) were reviewed. For the mean ADC value, we defined low (<1.2 × 10−3 mm2/s), intermediate (1.2 × 10−3 mm2/s ≤ ADC < 1.8 × 10−3 mm2/s) and high ADC (≥1.8 × 10−3 mm2/s).9

Review of Pathologic Report
The results of needle biopsy and surgical pathologic reports were analyzed. The histological subtype and pathological stage of the malignant component were reviewed. The results of the needle biopsy were classified as follows: (1) unsatisfactory specimen, (2) benign neoplasm, (3) pleomorphic adenoma, (4) uncertain neoplasm, and (5) malignant neoplasm.

Data Analysis
Statistical analysis was performed using SPSS version 18.0 (SPSS, Inc, Chicago, Illinois) and R Statistical Software (version 3.5.1; R Foundation for Statistical Computing, Vienna, Austria). Mann-Whitney U test were used for nonparametric statistics. The correlations of independent variables between the 2 groups were obtained through χ2 test or Fisher exact test.

Results
Clinical Features
The clinical characteristics of the 2 groups are shown in Figure 1. Patients with CXPA showed a higher age at the initial visit compared with those with pleomorphic adenoma (55.1 ± 15.5 vs 42.3 ± 14.5, respectively; P < .01). There were no significant differences between sexes, primary sites of tumors, and duration from symptom onset.


                        figure
                   
Figure 1. Demographics of the patients with carcinoma ex pleomorphic adenoma (CXPA) and pleomorphic adenoma. A, Patients with CXPA were older at the initial visit (55.1 ± 15.5 vs 42.3 ± 14.5, respectively; P < .01). B, Patients with CXPA visited the hospital later after symptoms developed, but without statistical significance (Median [IQR]: 36.0 [12.0-84.0] vs 12.0 [3.5-36.0], respectively; P = .10). C, The sex ratio between male and female was higher in CXPA, but without statistically significant difference (0.88 vs 0.78, P = .94).

The proportion of initial symptoms in patients was different; however, the manifestation was similar in the 2 groups when listing each symptom in order of percentage. In the pleomorphic adenoma group, the majority (95.9%; 212 of 221 patients) had palpable mass as the initial symptom, followed by pain (3.2%; 7 patients), incidental finding (3.2%; 7 patients), and swelling (0.9%; 2 patients). In the CXPA group, palpable mass was observed in 80% (12 of 15 patients), incidental finding in 20% (3 patients), and pain in 6.7% (1 patient). There were no patients with facial nerve paralysis preoperatively in both groups.

The primary site of CXPA and pleomorphic adenoma is shown in Figure 2. In 60% (9/15) of patients, tumors were developed in the parotid gland and 20% (3/15) in the submandibular gland (SMG). Two (13.3%) cases of minor salivary gland CXPA were in the tongue and the palate, respectively. In one case, the tumor developed in the neck node, and the patient underwent surgery for pleomorphic adenoma of SMG 20 years ago. These distributions appeared in the same order in pleomorphic adenoma; however, there was no primary pleomorphic adenoma in the lymph nodes.


                        figure
                   
Figure 2. Analysis according to the primary sites: (A) tumor location of carcinoma ex pleomorphic adenomas (CXPA) and pleomorphic adenoma. (B) The ratio of CXPA was inversely proportional to the size of salivary glands, but without statistical significance (P = .12). mSG indicates minor salivary gland; SMG, submandibular gland.

All 15 CXPA patients were initially treated with surgery. Five patients were treated with post-operative radiotherapy following surgery. Two patients had recurrence and both were salivary duct carcinoma. Distant metastasis occurred in 2 (22.2%) out of 9 patients during follow-up period (Supplemental Table 1).

Computed Tomography Findings
The features analyzed from CT scan are shown in Table 1. There was no significant difference in size between the 2 groups. Tumor multiplicity was observed only in the pleomorphic adenoma group (5.1%). There was a significantly higher incidence of regional lymph node enlargement greater than 5 mm in the CXPA group (46.2% vs 19.9%, P = .04). Ill-defined margin and necrosis or cystic change were higher in the CXPA group (33.3% vs 17.0%, 20.0% vs 7.2%, respectively), but without statistical significance (P = .07, P = .08, respectively).

Table
Table 1. Comparison of the Feature From CT Scans Between Carcinoma ex Pleomorphic Adenoma (CXPA) and Pleomorphic Adenoma.

Table 1. Comparison of the Feature From CT Scans Between Carcinoma ex Pleomorphic Adenoma (CXPA) and Pleomorphic Adenoma.


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Magnetic Resonance Imaging Findings
The features analyzed from MRI are shown in Table 2. Magnetic resonance images were available in 23 patients in the pleomorphic adenoma group and 7 in the CXPA group. There was no significantly proportional difference with respect to heterogeneity, low T1 signal, high T2 signal, enhancement, and extracapsular extension. However, the ratio of intermediate ADC was similar in both pleomorphic adenoma and CXPA groups (34.8% vs 33.3%, respectively), while that of high-ADC value was observed only in the pleomorphic adenoma group (60.9% vs 0.0%). The difference of proportion between the 2 groups according to the ADC values was observed to be significant (P = .01).

Table
Table 2. Comparison of the Feature From MRI Between and Carcinoma ex Pleomorphic Adenoma (CXPA) and Pleomorphic Adenoma.a

Table 2. Comparison of the Feature From MRI Between and Carcinoma ex Pleomorphic Adenoma (CXPA) and Pleomorphic Adenoma.a


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Classification of Ultrasonography-Guided Needle Biopsy Result
Needle biopsy was preoperatively evaluated in 192 of 221 pleomorphic adenoma patients and 12 of 21 CXPA patients. The result is shown in Table 3. In the pleomorphic adenoma group, there were no cases of misdiagnosis with malignancy. In the CXPA group, there were no cases of misdiagnosis with pleomorphic adenoma; however, one case was diagnosed as benign preoperatively. Five (41.7%) cases of 12 were diagnosed as malignant before surgery.


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Table
Table

Table
Table 3. Result of Needle Biopsy in Carcinoma ex Pleomorphic Adenoma (CXPA) and in Pleomorphic Adenoma.

Table
Table 3. Result of Needle Biopsy in Carcinoma ex Pleomorphic Adenoma (CXPA) and in Pleomorphic Adenoma.


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Discussion
Synopsis of Key Findings
Due to the rarity of CXPA, there have been a few studies comparing the clinical features of both diseases although the CXPA may arise from pleomorphic adenoma. This study compares of the clinical features between CXPA and pleomorphic adenoma and examine which features could be referenced in the differentiation of the 2 diseases.

Strength of the Study
A strength of this study was to integrate various clinical finding. This study found significant features in clinical manifestations, and parameters of CT and MRI which is the basic test performed for the treatment of salivary gland tumor.

Comparison With Other Studies
In a previous review, increased preoperative duration of pleomorphic adenoma increases the risk of malignant transformation into CXPA.3 The incidence of malignant transformation increased from 1.6% for the tumors with a clinical duration of <5 years to 9.6% for those with over 15 years.10 The longer the untreated period after diagnosis, the higher the likelihood of malignant transformation. Not surprisingly, a previous research effort addressed that the mean age of CXPA is 61 years,5 and another study with smaller number of patients showed that the median age of CXPA is 60 years.11 Our study showed that the average was slightly lower (55.1 years old) than these previous studies. When compared to pleomorphic adenoma, the mean age of diagnosis was significantly different by approximately 13 years (Figure 1A, 55.1 vs 42.3, respectively, P = .001). However, 6 (40.0%) of 13 patients diagnosed with CXPA were under the age of 50 years (Supplemental Table 1). The possibility of malignancy should not be ruled out due to young age. The time between first manifestation of symptoms and initial diagnosis was also longer in the CXPA group than in the pleomorphic adenoma group (Figure 1B, 36.0 months vs 12.0 months, respectively, P = .10), but without statistical significance. As reported in previous studies,4 it is difficult to know exactly when the mass was formed and at what speed it has grown.

The male-to-female ratio was similar in both diseases (Figure 1C). In this study, the ratio in the pleomorphic adenoma group was 0.78 and that in the CXPA group was 0.88, which did not present a significant difference between the 2 group. This result is different from previous reports, which have shown that pleomorphic adenoma is dominant in women, and CXPA is dominant in men.4,5,12 In this study, the number of males were slightly higher in the CXPA group than in the pleomorphic adenoma group.

The number of patients with CXPA according to location was 9 (60.0%), 3 (20.0%), 2 (13.3%), and 1 (6.7%) in order of parotid, SMG, minor salivary gland, and lymph node, respectively (Figure 2A); Each of 2 cases of minor salivary gland CXPA were in the tongue and the palate. The patient with CXPA in the neck node underwent surgery for pleomorphic adenoma of SMG 20 years ago. Except for the neck node, these distributions appeared in the same order in pleomorphic adenoma, however, when compared to pleomorphic adenoma according to the tumor location, the proportion of CXPA was 5.3%, 6.8%, and 25.0% in parotid, SMG, and minor salivary glands, respectively (Figure 2B). This finding is not only consistent with previous a study showing that CXPA predominantly affects the major salivary glands with a majority of cases noted in the parotid and SMG,3 but also adhered to the following trend: an inverse relationship between the size of salivary glands and the rate of malignancy; malignancy in 20% to 25% of parotid tumors; increased probability to 40% to 50% in the SMG and 50% to 81% in the sublingual and minor salivary glands.13-15 However, the proportion is not perfectly matched with previous reports because only 2 types of histological diagnosis were considered in this study.

According to previous research regarding the characteristics of CT scans for malignant tumor of the parotid gland, there was no particular feature that was able to consistently suggested malignancy.16 Similar results were obtained in this present study; it was difficult to find any distinct feature that suggested malignancy. However, lymph node >5 mm also showed a statistically significant difference between the two diseases (Table 1, P = .04).

With respect to tumor size, previous reports showed that 42% of CXPA and 10% of pleomorphic adenoma had a diameter of more than 4 cm; and 17% of CXPA and 40% of pleomorphic adenoma had a diameter of less than 2 cm.4 In this study, 14.3% of CXPA and 7.3% of pleomorphic adenoma had a diameter of greater than 4 cm; and 7.1% of CXPA and 29.2% of pleomorphic adenoma had a diameter of less than 2 cm. In addition to these similar trends, tumor size showed statistically significant difference (P = .01). However, given that the difference of the mean value of the tumor size was so small (CXPA: 2.9 cm, pleomorphic adenoma: 2.2 cm), it may be limiting to use this as a reference for diagnosis.

The ambiguity of features appeared to be similar in MRI. Heterogeneity, differences of the signal intensity according to the protocols, enhancement and extracapsular extension were not determined to be features that can distinguish between the 2 groups. Only the ADC value showed to have a significant difference between the groups (P = .01). As previously reported, benign tumors have higher mean ADC values than malignant tumors generally.9 In addition, a previous study showed that the mean ADC for pleomorphic adenomas was 1.74 ± 0.37 × 10−3 mm2/s, and that for malignant tumors was 1.04 ± 0.35 × 10−3 mm2/s.17

Our results also showed that none of the CXPA patients had a high ADC value; on the contrary, most of the pleomorphic adenoma patients had an intermediate to high ADC value. Therefore, diffusion-weighted MRI for calculating the mean ADC value can be used as a modality for the initial work up and for follow-up in cases of recurrence of benign pleomorphic adenoma or when a patient is not able to receive immediate surgical treatment due to any circumstances. If the initial ADC value is not high, or if there is a decrease in an initially high ADC value, then a surgical resection should be considered to remove any potentially malignant tumors.

Regarding accuracy of needle biopsy, the detailed figures are slightly different depending on the literature.7,8,18 Similarly, the result of a needle biopsy in this study (Table 3) also suggests that there could be various results and therefore, inconclusive.

Clinical Applicability of the Study
Carcinoma ex pleomorphic adenoma is a rare; a yearly incidence rate of 0.17 tumors per 1 million persons.3 In a nationwide study, pleomorphic adenoma of the salivary gland transforms into CXPA in approximately 1.8% to 6.2% of cases.19

Treatment of pleomorphic adenoma is mostly terminated by surgery alone, but treatment of CXPA is surgical parotidectomy with neck dissection. Moreover, postoperative radiotherapy for loco regional control can also be considered for patients with CXPA.20 But diagnostic accuracy of fine needle aspiration biopsy or core-needle biopsy of CXPA is lower than 50%.4,7,21 Therefore, in case of preoperative or postoperative recurrence of pleomorphic adenoma, considering the possibility of malignant transformation in advance may be important in setting the scope of the surgical extent. In these regards, the significant factors revealed in this study may be references for the differentiation of CXPA.

Conclusion
From this study, if a patient is diagnosed with pleomorphic adenoma, the following features should be considered in the evaluation of the possibility of CXPA: (1) old age, (2) minor salivary gland tumor, (3) regional lymph node enlargement (>5 mm), and (4) low ADC findings.

Authors’ Note
Jungirl Seok and Se Jin Hyun contributed equally to this work. Hyojin Kim and Young Ho Jung contributed equally to this work.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD
Young Ho Jung  https://orcid.org/0000-0002-3399-8167

Supplemental Material
Supplemental material for this article is available online.

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