J Oral Maxillofac Surg 70:2701-2712, 2012

Metachronous Manifestation of Carcinoma Ex Pleomorphic Adenoma in a Buccal Minor Salivary Gland and the Contralateral Parotid Gland: A Case Report and Review of the Literature Kazuo Sano, DDS, PhD,* Shuichi Fujita, DDS, PhD,† Joji Sekine, DDS, PhD,‡ Masataka Uehara, DDS, PhD,§ Noriyuki Sakihama, MD, PhD,储 Tomayoshi Hayashi, MD, PhD,¶ Hitoshi Yoshimura, DDS, PhD,# and Takayoshi Tobita, DDS, PhD** Carcinoma ex pleomorphic adenoma (Ca-ex-PA) has been defined as a pleomorphic adenoma from which an epithelial malignancy is derived.1 It is also known as carcinoma arising in a benign mixed tumor, carcinoma ex benign pleomorphic adenoma, carcinoma arising in a pleomorphic adenoma, and malignant mixed tumor. In files of the Armed Forces Institute of Pathology reviewed since 1970, Ca-ex-PA accounted for 9.5% of all pleomorphic adenomas and 6% of all malignant salivary gland tumors.2 Most salivary gland neoplasms present as a single mass involving only one gland, and multiple salivary gland tumors occur rarely.3 In 1989, Gnepp et al4 reported multiple salivary gland tumors of various combinations. Among these, the occurrence of multiple malignant salivary gland tumors was quite unusual. In 2008, Whitt et al5 reviewed 31 cases of Received from the Division of Dentistry and Oral Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan *Professor, Division of Dentistry and Oral Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. †Associate Professor, Division of Oral Pathology and Bone Metabolism, Nagasaki University Graduate School of Biomedical Science, Course of Medical and Dental Science. ‡Professor, Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Izumo, Japan. §Former Lecturer, Department of Regenerative Oral Surgery, Nagasaki University Hospital. 储Former Lecturer, Department of Otolaryngology and Head and Neck Surgery, Nagasaki University Graduate School of Biomedical Science, Course of Medical and Dental Science.

multiple malignant salivary gland neoplasms reported in the worldwide literature. In their review, bilateral acinic cell adenocarcinoma was the most frequent combination of multiple salivary gland malignancy, accounting for 14 cases (10 synchronous and 4 metachronous). Multiple malignant salivary gland tumors of other combinations have occurred sporadically, and there has been only 1 case of synchronous manifestation of Ca-ex-PAs in the parotid and submaxillary glands.6 As yet, no metachronous occurrence of Caex-PAs in salivary glands has been reported. The present report describes an extremely rare case of a metachronous manifestation of Ca-ex-PA of a buccal minor salivary gland extending into the temporal fossa, and 3 years later, of the contralateral parotid gland. Moreover, a review of the literature on the histologic types and locations of multiple malig¶Associate Professor, Department of Pathology, Nagasaki University Hospital, Nagasaki, Japan. #Assistant Professor, Division of Dentistry and Oral Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. **Lecturer, Division of Dentistry and Oral Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. Address correspondence and reprint requests to Dr Sano: Division of Dentistry and Oral Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; e-mail: [email protected] © 2012 American Association of Oral and Maxillofacial Surgeons

0278-2391/12/7011-0$36.00/0 doi:10.1016/j.joms.2011.12.016

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FIGURE 1. Intraoral image showing a 30 ⫻ 30 mm elastic hard mass in the right buccal mucosa. Sano et al. Metachronous Carcinoma Ex Pleomorphic Adenoma. J Oral Maxillofac Surg 2012.

nant salivary gland tumors and the histologic subtypes of the malignant component of the Ca-ex-PA is presented.

Report of Case A 71-year-old woman was referred to the Second Department of Oral and Maxillofacial Surgery, Nagasaki University Hospital of Dentistry, because of a painless swelling of the right buccal mucosa in August 1997. The patient first noticed this slowly growing, expansile mass 7 months previously. Her medical history was noncontributory. Her face was slightly asymmetric because of the right buccal swelling, but no trismus was observed. Intraoral examination disclosed a 30 ⫻ 35 mm firm mass with redness in the right buccal mucosa (Fig 1). Laboratory data were within the normal ranges. Enhanced computed tomographic (CT) scan showed a mass with heterogeneous enhancement extending from the anterior part of the right ascending ramus to the right temporal fossa (Fig 2A). The right maxillary sinus was narrowed by compression of the mass; however, the right orbital floor was not destroyed. There was no detectable swelling of the cervical lymph nodes. T2-weighted magnetic resonance (MR) image showed a 70 ⫻ 40 ⫻ 40 mm heterogeneous mass with an internal high-intensity signal (Fig 2B, C). In particular, a component with highsignal intensity on the T2-weighted image was observed in the lower part of the mass located in the anterior part of the right ascending ramus. Ultrasonography of the bilateral neck showed no lymphadenopathy. These results collectively suggested a malignant tumor of the right buccal mucosa and a biopsy was taken from the right buccal mucosa. The biopsy specimen contained a piece of the tumor covered with a fibrous capsule. The tumor was composed of polyhedral or plasmacytoid cells arranged in solid nests. Ductal structures containing eosinophilic secreted material were intermingled in the tumor (Fig 3A). The tumor included hyalinized or myxoid matrices, and the tumor cells that had been separated from the solid or tubular structures were scattered in these extracellular matrices (Fig 3B). No atypia was noticed, and very few mitotic figures were found. These findings were consistent with a histologic diagnosis of benign pleomorphic adenoma of the buccal minor salivary gland.

METACHRONOUS CARCINOMA EX PLEOMORPHIC ADENOMA Although the biopsy specimen was histologically diagnosed as benign pleomorphic adenoma, tumor resection using transfacial and temporal approaches was performed for a suspected malignant tumor of the buccal mucosa extending into the temporal fossa as detected by CT and MR imaging examinations. The tumor with an appropriate surgical margin was resected en bloc with part of the right maxilla and the right coronoid process. A split-thickness skin graft from the thigh to the raw surface of the buccal mucosa was performed to prevent postoperative trismus. The resected specimen was 70 ⫻ 40 ⫻ 35 mm and weighed 50 g. Macroscopically, the cut surface of the removed tumor exhibited a solid yellowish-white mass, including necrotic and hemorrhagic foci. Histologically, the tumor was composed of a mixture of well-encapsulated benign pleomorphic adenoma, like the biopsy specimen, and a solid proliferation of round cells, including hyperchromatic nuclei. The latter component infiltrated into the adipose tissue and merged with inner necrotic foci. These histologic findings indicated malignancy. The malignant area also included small nests or trabeculae comprised of plump clear cells (Fig 4A). The benign pleomorphic adenoma and the malignant part were connected to each other (Fig 4B). The distance from the tumor capsule to the invasive front, as one of the histomorphologic indexes,7 was 7 mm, but this invasion did not reach the surgical margin. Immunohistochemically, the tumor cells in the both components with the exception of duct luminal cells showed coexpression of the broad-spectrum cytokeratins AE1/AE3 (Fig 4C), S-100 protein, and ␣-smooth muscle actin (Fig 4D). These findings indicated myoepithelial carcinoma arising from a pre-existent benign pleomorphic adenoma. The pathologic diagnosis of the resected tumor was an invasive type of Ca-ex-PA of the buccal minor salivary gland. The postoperative course was uneventful, and no additional therapy such as chemotherapy or radiotherapy was carried out. Although slight trismus and contraction in the right cheek were observed, no facial paralysis was observed. The patient wore a maxillary prosthesis and showed no masticatory disturbance. In January 2001, enhanced CT image visualized a mass of about 7 mm in diameter in the left parotid gland (Fig 5A), and the patient was referred to the Department of Otolaryngology and Head and Neck Surgery, Nagasaki University Hospital. Because of the patient’s advanced age, it was decided that the growth of the mass would be followed. However, the mass gradually enlarged, and an enhanced CT image in June 2003 showed an enlarged mass with a central low-density area and an irregular ring enhancement in the left parotid gland (Fig 5B). Examination disclosed a 20 ⫻ 20 mm mobile swelling in the left parotid gland and an intact facial nerve. Cervical lymphadenopathy was not observed. Cytologic results of fine-needle aspiration were suggestive of a benign parotid gland tumor. The patient underwent a left deep lobe parotidectomy under general anesthesia in October 2003. The buccal branch of the left facial nerve was sacrificed, because it was involved in the tumor. The surgical specimen showed a tumor demarcated from the parotid gland by a thin fibrous capsule. The tumor was composed of peripheral vital parenchyma and inner broad necrotic areas (Fig 6A). Small foci of double cell-layered tubular structures accompanied by hyalinized stroma were noticed in the vital area. This component exhibited subtle atypia, suggesting a benign pleomorphic adenoma. However, in some areas, solid nests or epithelial trabeculae exhibiting cells with hyperchromatic nuclei were also noted, suggesting the possibility of a malignancy (Fig 6B).

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FIGURE 2. A, Preoperative enhanced computed tomogram showing a mass with a heterogeneous enhancement extending from the anterior part of the right ascending ramus to the right temporal fossa. B, Axial and C, coronal T2-weighted magnetic resonance image showing a 70 ⫻ 40 ⫻ 40 mm heterogeneous mass with internal high-signal intensity. Sano et al. Metachronous Carcinoma Ex Pleomorphic Adenoma. J Oral Maxillofac Surg 2012.

Immunohistochemical examination for MIB-1 (clone of Ki-67 available for the paraffin-embedded tissue) showed a mixture of restricted pleomorphic adenoma with a low density of proliferative cells and a broad malignant area, including numerous proliferative cells (Fig 6C). Malignant areas also displayed areas of necrosis and invasion of the adjacent parotid lymph node (Fig 6D). The lymph node invasion focus was measured to be 1 mm from the tumor capsule (Fig 6D). Moreover, perineural infiltration was often observed in the tumor (Fig 6E). The surgical margin was free from the carcinoma. Most tumor cells, except for the

duct luminal cells, were immunohistochemically positive for the broad-spectrum cytokeratins AE1/AE3, S-100 protein (Fig 6E), and ␣-smooth muscle actin. Therefore, the tumor was diagnosed as myoepithelial Ca-ex-PA. The perineural invasion of the carcinoma was considered an indication for postoperative radiotherapy. However, the patient did not undergo radiotherapy because of her advanced age. In September 2006, recurrence was observed in the left residual parotid gland. Examination showed a 40 ⫻ 25 mm elastic hard mass in the left parotid gland. The mass approximated the overlying skin. The patient under-

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FIGURE 3. Biopsy from buccal mucosa. A, Well-encapsulated tumor composed of a solid tumor, including ducts and myxoid extracellular matrix (C, capsule; hematoxylin and eosin stain; original magnification, ⫻10). B, Tumor cells detached from solid (S) or from trabecular (arrows) structures were scattered in the myxoid extracellular matrix (hematoxylin and eosin stain; original magnification, ⫻20). Sano et al. Metachronous Carcinoma Ex Pleomorphic Adenoma. J Oral Maxillofac Surg 2012.

FIGURE 4. Tumor removed from buccal mucosa. A, The malignant component invaded the peripheral adipose tissue (arrowheads). Clear cells with hyperchromatic round nuclei were included in the nests (arrows) (hematoxylin and eosin stain; original magnification, ⫻20). B, The benign pleomorphic adenoma (right) changed into a malignant area (left) (hematoxylin and eosin stain; original magnification, ⫻20). C, Malignant tumor cells, including clear cells, showed an immunohistochemical reaction with cytokeratin AE1/AE3 (original magnification ⫻40). D, Most malignant tumor cells were immunohistochemically positive for ␣-smooth muscle actin (original magnification ⫻40). Sano et al. Metachronous Carcinoma Ex Pleomorphic Adenoma. J Oral Maxillofac Surg 2012.

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FIGURE 5. A, Computed tomogram obtained in 2001 showing a mass of about 7 mm in diameter in the left parotid gland. B, Computed tomogram obtained in 2003 showing an enlarged mass with a central low-density area and an irregular ring enhancement in the left parotid gland. Sano et al. Metachronous Carcinoma Ex Pleomorphic Adenoma. J Oral Maxillofac Surg 2012.

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FIGURE 7. Recurrent tumor of the left parotid gland had a squamous cell carcinoma component in addition to myoepithelial carcinoma. There was obvious keratinization of the tumor cells (hematoxylin and eosin stain; original magnification, ⫻20). Sano et al. Metachronous Carcinoma Ex Pleomorphic Adenoma. J Oral Maxillofac Surg 2012.

went tumorectomy, which included the residual superficial lobe, the facial nerve branches, and the overlying skin; left neck dissection and nerve grafting were also performed under general anesthesia. The recurrent tumor exhibited a lobulated nodule demarcated from the parotid gland. Similar to the primary tumor, the recurrent tumor included necrotic tissue in the central portion; the vital parenchyma was composed of myoepithelial carcinoma. In addition, there were squamous cell carcinoma components containing keratin pearls (Fig 7), and obvious benign features were not recognized. The tumor invaded the subcutaneous adipose tissue, and the distance from the infiltration front to the incomplete capsule was 2 mm. No perineural invasion or lymph node metastasis was found. The histologic diagnosis of recurrent Ca-ex-PA was made. Her postoperative course was uneventful except for left facial paralysis. No signs of metastasis or tumor recurrence in the buccal mucosa or left parotid regions were observed 13 and 4 years after the operations, respectively.

Discussion At present, 37 cases of multiple malignant salivary gland tumors have been reported in the literature, making the present case the 38th (Table 1).4-6,8-36 The

number of cases of synchronous and metachronous malignant salivary gland tumors are 24 and 14, respectively. The most common combination of tumor locations is the bilateral parotid glands (25 cases), followed by the same parotid gland (4 cases), different minor salivary glands (4 cases), and parotid and submandibular glands (3 cases). The combination of acinic cell carcinomas (16 cases: 11 synchronous and 5 metachronous) is the most common histologic type, followed by mucoepidermoid carcinomas (4 cases: 3 synchronous and 1 metachronous) and adenocarcinomas (3 cases: 1 synchronous and 2 metachronous). Although a case of synchronous Ca-ex-PAs in different major salivary glands has been reported,6 to the best of the authors’ knowledge, the present case is the first report of metachronous Ca-ex-PAs involving the contralateral minor and major salivary glands. From a chronologic point of view, the second neoplasm is synchronous if it is diagnosed within 6 months of the diagnosis of the initial tumor, and metachronous if it is diagnosed after a period of 6 months.37,38 In the present case, the second contralateral parotid tumor was not detected on the CT image when the first tumor in the buccal mucosa was detected. Furthermore, the parotid tumor was not considered a metastasis from the buccal minor salivary gland tumor, because the 2 tumors had different histologic features. Namely, the myoepithelial carcinoma was observed in the both lesions, but clear cells were included in the buccal minor salivary gland tumor, but not in the parotid tumor. In addition, postoperative radiation therapy was not performed for the first tumor because of the presence of an appropriate surgical margin. Therefore, the parotid tumor was not induced by radiation. Another rare entity of salivary gland tumors that shows metachronous manifestation is the metastasizing pleomorphic adenoma.39 A metastasizing pleomorphic adenoma is, as defined by the World Health Organization, “a histologically benign pleomorphic adenoma that inexplicably manifests local or distant metastasis.”40 Primary and metastatic foci of metastasizing pleomorphic adenoma lack histologically malignant components.40 The most common site of these tumors is the parotid gland, followed by the subman-

4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™ FIGURE 6. Tumor of left parotid gland. A, The tumor (right) was demarcated from the atrophic parotid gland. The tumor nodules contained broad necrotic tissue (N) in the central portion (hematoxylin and eosin stain; scale bar, 10 mm). B, Tubular patterns showing a double cell-layered structure indicated a benign feature (right). Trabecular and solid patterns were composed of atypical cells with a high nuclear-cytoplasmic (N/C) ratio and hyperchromatic nuclei (left) (hematoxylin and eosin stain; original magnification, ⫻20). C, The density of Ki-67-positive cells was increased in the malignant trabecular structures, including large nuclei (arrows), in contrast to ductal structures with benign features (arrowheads) (Ki-67 [MIB-1], original magnification ⫻20). D, Solid malignant elements (arrows) invaded the parotid lymph node. Direct infiltration rather than metastasis was considered because the lymph node capsule coalesced with the tumor capsule (hematoxylin and eosin stain; original magnification, ⫻5). E, S-100 protein was expressed in the malignant tumor cells. The nerve bundle (N) was also positive (S-100 protein; original magnification, ⫻40). Sano et al. Metachronous Carcinoma Ex Pleomorphic Adenoma. J Oral Maxillofac Surg 2012.

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Table 1. NUMBER OF MULTIPLE MALIGNANT SALIVARY GLAND TUMORS ACCORDING TO THE COMBINATION OF HISTOLOGIC TYPES AND LOCATIONS INCLUDING DATA FROM THE PRESENT CASE

Cases (n) Synchronous occurrence ACCC and ACCC MEDC and MEDC Ca-ex-PA and AC PLGA and PLGA AC and AC ADCC and ADCC ADCC and Se-Ca BCAC and ADCC/EMC Ca-ex-PA and Ca-ex-PA EMC and EMC Total synchronous cases Metachronous occurrence ACCC and ACCC AC and AC MEDC and ADCC AC and SCC ADCC and ADCC Ca-ex-PA and Ca-ex-PA EMC and EMC MEDC and MEDC Total metachronous cases Total

11 3 2 2 1 1 1 1 1 1 24 5 2 2 1 1 1 1 1 14 38

ParotidParotid 109-16* 218,19 221,22

Parotid (Same Gland)

ParotidSMG

ParotidMinor

SMGSMG

MinorMinor

117 20

1

223† 18 124 125 14 16 26

1 16

3

2

3

514,27-29‡ 130

131 132

15

33

1 134 1§ 135 136 9 25

1 4

1 3

1 1

1 1

1 4

Abbreviations: AC, adenocarcinoma; ACCC, acinic cell carcinoma; ADCC, adenoid cystic carcinoma; BCAC, basal cell adenocarcinoma; Ca-ex-PA, carcinoma ex pleomorphic adenoma; EMC, epithelial-myoepithelial carcinoma; MEDC, mucoepidermoid carcinoma; Minor, minor salivary gland; PLGA, polymorphous low-grade adenocarcinoma; SCC, squamous cell carcinoma; Se-Ca, sebaceous carcinoma; SMG, submandibular gland. *Two cases in Diamant et al12 and Enroth et al.14 †Two cases in Clayton et al.23 ‡Two cases in Turnbull et al.29 §Present case. Sano et al. Metachronous Carcinoma Ex Pleomorphic Adenoma. J Oral Maxillofac Surg 2012.

dibular gland and palate.41 Metastasis through a hematologic or lymphatic route to the bone, lung, or lymph nodes has been reported to occur after recurrence of the primary tumor.39-42 Therefore, resection of the primary tumor with wide surgical margins is recommended.42 In the present case, a metastasizing PA can be ruled out because of the coexistence of the benign and malignant components in the first buccal and second parotid tumors. The authors reviewed the histologic subtypes of the malignant component in the Ca-ex-PA in the existing literature before publication of the World Health Organization’s Histological Typing of Salivary Gland Tumours, 2nd edition, by Seifert and Sobin in 1991.43 To avoid any confusion from the use of different classification standards, the authors selected only the relevant cases from the literature since 1991 (Table 2).44-71 Among the 219 cases, adenocarcinoma (79 cases; 36.1%) was the most common histologic subtype of Ca-ex-PA, followed by salivary duct carcinoma (57 cases; 26.0%), myoepithelial carcinoma (28

cases; 12.8%), adenoid cystic carcinoma (14 cases; 6.4%), and mucoepidermoid carcinoma (13 cases; 5.9%). Other subtypes were exceedingly rare (ⱕ5 cases). In the present case, the malignant component of the Ca-ex-PA in the buccal minor salivary gland and the parotid gland was myoepithelial carcinoma; however, the recurrent parotid tumor included the squamous cell carcinoma component. As Farman et al72 pointed out, the recurrent parotid tumor was considered to represent combined carcinomas arising in a pleomorphic adenoma. Tumor duration and recurrence are risks for the malignant transformation of a benign pleomorphic adenoma.2 A comparison of the patient age between patients with Ca-ex-PA and those with benign pleomorphic adenoma among cases of the Armed Forces Institute of Pathology2 showed that carcinomas occur on average about 12 years later than adenomas (47.2 vs 59.4 yrs). In the present case, the first buccal and second parotid manifestations of the tumors occurred at 71 and 75 years of age, respectively. The rapid

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Table 2. DEFINITIVE HISTOLOGIC SUBTYPES OF THE MALIGNANT COMPONENT IN CARCINOMA EX PLEOMORPHIC ADENOMA AS CITED IN THE LITERATURE SINCE 1991

Study Akgüner et al44 Alós et al45 Cohn et al46 Daneshbod et al47 Di Palma et al48 El-Naggar et al49 Ersöz et al50 Etit et al51 Hellin-Meseguer et al52 Ide et al53 Iino et al54 Jacobs55 Kämmerer et al56 Katabi et al57 Klijanienko et al58 Kunimura59 Lewis et al60 Lüers et al61 Matsubayashi and Yoshihara62 McCluggage et al63 McNamara et al64 Nakamori et al65 Parwani et al66 Said and Campana67 Tralongo et al68 Yang et al69 Yoshihara et al70 Zbären et al71 Total Present case

Cases (n) AC SDC MEC ADCC MEDC ADSQC EMC UDC SCC PLGA MMT ACCC BCAC BCC CCSC MEC/AC OCC SDC/SCC Se-Ca 1 2 1 1 1 1 1 1 1 1 1 1 1 43 24 1 70 19 10 1 1 1 1 1 1 7 1 24 219 1

1 2 1 1 1 1 1 1 1 1 1 1 1 2 7 1 31 14 9

25 2

15

24

2 2

1 2

8

3 3

2 5

1

1

1

3

1 1

1 1

1 1

5 1 6 79

1 1 1 1 4 57

1 28 2*

1 5 14

4 13

5

1 5

4

1 2

2

2

1 1

1

1 1

1

1

1

1

1

Abbreviations: AC, adenocarcinoma; ACCC, acinic cell carcinoma; ADCC, adenoid cystic carcinoma; ADSQC, adenosquamous cell carcinoma; BCAC, basal cell adenocarcinoma; BCC, basal cell carcinoma; CCSC, clear cell squamous cell carcinoma; EMC, epithelial-myoepithelial carcinoma; MEC, myoepithelial carcinoma; MEDC, mucoepidermoid carcinoma; MMT, malignant mixed tumor (carcinosarcoma or sarcomatoid carcinoma); OCC, oncocytic carcinoma; PLGA, polymorphous low-grade adenocarcinoma; SCC, squamous cell carcinoma; SDC, salivary duct carcinoma; Se-Ca, sebaceous carcinoma; UDC, undifferentiated carcinoma. *Two metachronous manifestations, in the buccal minor salivary gland and in the contralateral parotid gland.

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2710 growth of a previously stable mass is considered a sign of potential malignant transformation.73 In the present case, the patient noticed a slowly expansile mass in the buccal mucosa 7 months before the initial visit. However, it was unclear when the malignant transformation occurred in the buccal tumor. In the present case, for the preoperative diagnosis of the buccal tumor, a preoperative biopsy was performed and a pathologic diagnosis of pleomorphic adenoma was obtained. However, resection of the tumor was performed under a strong suspicion of malignant tumor because of the preoperative image analysis. The surgical specimen was pathologically diagnosed as Ca-ex-PA. Therefore, the preoperative incisional biopsy was not representative, but a sampling error. In the CT diagnosis of head and neck lesions, ring or rim enhancement on contrast-enhanced CT imaging has been observed in inflammatory masses,74 parotid abscesses,75 Warthin tumors,76 basal cell adenomas,77 and metastatic cervical lymph nodes.78 In the present case, an enlarged mass with a central lowdensity area and an irregular rim enhancement was observed (Fig 5B). In contrast, Som and BrandweinGensler79 described the aggressive area in the Caex-PA as having “a necrotic center, thick, irregular walls, and infiltrating margins on CT.” Comparing CT with pathologic findings in the parotid tumor of the present case, the low-density area and irregular rim enhancement were in accordance with broad necrotic areas and peripheral viable tumor cells (Fig 6A), respectively. Accordingly, the irregular ring enhancement on the CT image was considered to reflect this histopathologic condition. Lüers et al61 retrospectively analyzed the preoperative diagnosis of Ca-ex-PA of the parotid gland using ultrasound and fine-needle aspiration, with the addition of CT/MR imaging where required. Nine of 22 patients were thought to have a pleomorphic adenoma before operation. Eight patients were suspected of having a parotid malignancy, and Ca-ex-PA was suspected in only 3 cases. Said and Campana67 reported a case of myoepithelial Ca-ex-PA, in which the findings from a preoperative incisional biopsy and those from an intraoperative frozen section were consistent with pleomorphic adenoma. Thus, the pre- or intraoperative diagnosis of Ca-ex-PAs is difficult in cases in which the malignant area is tiny and/or beyond the reach of needle aspiration cytology or transmucosal incisional biopsy. Eneroth et al80 emphasized the risk of overlooking the presence of infiltrative growth if there is an inadequate margin of tissue around the salivary gland tumor. In the present case, a combined transfacial and temporal approach was used and was considered a useful technique to resect the buccal tumor extending into the

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temporal fossa. This approach was useful because the tumor could be resected with an appropriate margin in the temporal fossa under direct observation. In the postoperative follow-up, the resected site could be observed directly, and the maxillary prosthesis provided the patient with good mastication. Ca-ex-PA historically has been considered a highgrade malignancy.81 Of late, “intracapsular” Ca-ex-PA and minimally invasive Ca-ex-PA (⬍1.5 mm of invasion) are considered indolent variants,1,81,82 and these should not be considered equivalent to the typical Ca-ex-PA.81 The recommendations81 for reporting on Ca-ex-PAs include the histologic type/grade, percentage of carcinoma, and extent of invasion of the carcinomatous component, ie, intracapsular, minimally invasive, and invasive. In addition, caution should be taken to consider the fact that minimally invasive carcinomas are capable of metastasis, as well as to ensure that treatment of patients with minimally invasive carcinoma is based on margin status and the presence of perineural invasion; if either is present, then re-excision and/or radiation therapy need to be considered.83 In the present patient, the buccal tumor was invasive (7 mm), and the contralateral parotid tumor was minimally invasive (1 mm), but had perineural invasion. Additional radiotherapy for the parotid tumor was considered necessary because of the perineural invasion; however, the patient did not undergo radiotherapy because of her advanced age. Subsequently, the recurrent parotid tumor was resected successfully with a sufficient surgical margin, and there were no metastases or recurrences of either tumor during the follow-up period. In conclusion, patients with a malignant salivary gland tumor should be followed because of the potential for multiple tumor occurrences. Acknowledgments The authors thank Prof Izumi Asahina, Division of Oral and Maxillofacial Surgical Reconstruction and Functional Restoration, and Prof Tohru Ikeda, Division of Oral Pathology and Bone Metabolism, Nagasaki University Graduate School of Biomedical Science, Course of Medical and Dental Science, for permitting access to the patient’s records. The authors are indebted to Prof Hirohiko Kimura, Division of Radiology, Department of Radiology and Laboratory Medicine, Faculty of Medical Sciences, University of Fukui, for helpful suggestions on the computed tomographic diagnosis.

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