Adjuvant conundrum in central mucoepidermoid carcinoma of the mandible: case presentation and literature review

Abstract

The cornerstone modality of treatment of central mucoepidermoid carcinoma (CMEC) of the mandible is surgery, optimally, an en bloc resection with/without segmental or hemimandibulectomy. Notwithstanding the documentation of a survival benefit in few case reports with the addition of postoperative radiotherapy in carefully selected high-risk patients, there does not exist a clearly defined consensus regarding the role of adjuvant radiotherapy. We report the case of a 49-year-old man who presented with right lower jaw swelling which on imaging was found to be a multiloculated lesion causing bony expansion and cortical destruction of the mandible and was diagnosed with CMEC after radiological and histopathological criteria were met. He underwent right hemimandibulectomy and histopathology showed squamous and mucinous cells with positive mucicarmine staining and characteristic immunohistochemistry markers confirming the diagnosis of CMEC. He subsequently underwent adjuvant radiotherapy and is disease free 5 years since treatment completion.

Background

Mucoepidermoid carcinoma (MEC), the most common malignant salivary gland tumour, is known to originate from ectopic salivary gland tissue.¹ Very rarely though, it can also originate as an intraosseous variant from the mandible or maxilla, known as ‘Central Mucoepidermoid Carcinoma’ (CMEC) or ‘Intraosseous mucoepidermoid carcinoma’. This entity comprises only 2%–3% of all MECs reported.² Lepp in 1939 first reported a CMEC of the mandible³; however, the first review was published only in 1968, by Smith et al.⁴

Clinical presentation, radiological features and histology of CMEC closely mimics that of other benign and malignant tumours of the jaw, rendering correct diagnosis, prognostication and management a challenge. The rarity of occurrence, with only about 150 cases reported, has further contributed to a lack of consensus regarding the optimal treatment. Surgery is the cornerstone modality in the management of CMECs; however, the role of adjuvant radiotherapy has continued to be controversial until the recent documentation of an improvement in survival in selected group of patients with high-risk features.⁵

We report a case of CMEC of the mandible, managed by surgery followed by adjuvant radiotherapy, and review the literature to further the understanding of the biological behaviour, diagnosis and management of these neoplasms.

Case presentation

A 49-year-old man of African origin presented with the complaint of a painless swelling in the right lower jaw since 3 months. On clinical examination, no accompanying swelling was identified and the overlying skin was intact. Panoramic radiographic examination revealed a large radiolucent lesion with a few loculations on the right side of the mandible (figure 1). Contrast-enhanced CT scan revealed a 4×4.7×3.3 cm soft tissue necrotic mass lesion arising from and causing expansion as well as cortical destruction of the right ramus and angle of mandible, with no other accompanying lesions or cysts (figure 2). He was subsequently planned for radical surgery after regional and distant metastases were ruled out.

Figure 1.

Cropped radiograph showing radiolucent and loculated mandibular lesion extending from the first molar area to the ascending ramus.

Figure 2.

Cropped CT image showing mandibular mass lesion (arrowhead) with expansion and complete destruction of medial (buccal) cortex, partial destruction of lateral cortex and central necrosis.

He underwent right hemimandibulectomy with reconstruction with mandibular plate with condyle and muscle flap cover. Intraoperatively, soft tissue lesion was seen in the region of angle of mandible, completely destroying medial cortex. In view of the tumour being present in the segmental resection margin, hemimandibulectomy was done. Histopathological report was suggestive of a benign odontogenic tumour, more likely to be squamous odontogenic tumour rather than ameloblastoma, with free margins, although the tumour was seen at inked margins with squamoid and mucinous cells (figure 3). Tumour cells showed positive staining for cytokeratin and were negative for Smooth Muscle Actin (SMA). Proliferative activity (Ki67 index) was low.

Figure 3.

High magnification (40×) showing both squamoid as well as mucinous cells.

Slides and tissue blocks were reviewed at AmeriPath, Indianapolis and a benign odontogenic tumour was ruled out in favour of an infiltrating epithelial neoplasm. The nature of architectural pattern of growth and occasional cytoplasmic vacuoles raised the possibility of a CMEC. Strong and convincing mucicarmine positivity (figure 4) was seen, and on immunohistochemical (IHC) evaluation, the tumour cells were positive for high molecular weight cytokeratin and cytokeratin AE1/AE3 (figure 5). The tumour cells were negative for p63. The MIB-1 nuclear proliferation index was variable throughout the tumour but generally low with a few foci of up to 5% labelling. These reactions supported the diagnosis of a CMEC, intermediate grade (ie, grade II in a I to III grade scale). Blocks were reviewed in-house and our pathology team concurred with the diagnosis of CMEC.

Figure 4.

Mucicarmine staining.

Figure 5.

Immunohistochemical expression of HMW-CK and CK-AE1/AE3.

He was subsequently planned for adjuvant radiotherapy using Intensity Modulated Radiotherapy (IMRT) with daily image guidance after multidisciplinary team discussion. Treatment was planned using contrast-enhanced planning CT scan on Eclipse (Varian Medical Systems, Palo Alto, California, USA) treatment planning system. Treatment was delivered on the Novalis-Tx linear accelerator after quality assurance protocol completion. A dose of 54 Gy was prescribed to the preoperative extent of the tumour, remaining mandible and the neck nodes, delivered in 1.8 Gy per fraction. A 12 Gy boost to the tumour bed was then delivered in 2 Gy per fraction. The treatment was completed in 53 days and the worst skin and mucosal reactions seen were grade 2.

Outcome and follow-up

Regular follow-up ensued incorporating 3 monthly clinical examination and 6 monthly imaging (CT scan) for first 2 years followed by yearly assessments thereafter. The patient continues to be disease free 5 years post-treatment.

Discussion

CMEC is an uncommon entity first reported in 1939 by Lepp³ and was included in the classification of primary intraosseous carcinomas as type 4 in 1989 by Waldron and Mustoe⁶ (table 1).

Table 1.

Classification of PIOC (primary intraosseous carcinoma)

Classification of PIOC6
Type 1	PIOC ex odontogenic cyst
Type 2a	Malignant ameloblastoma
Type 2b	Ameloblastic carcinoma arising de novo, ex ameloblastoma or ex odontogenic cyst
Type 3	PIOC arising de novo: (1) keratinising type; (2) non-keratinising type
Type 4	Central MEC

CMECs have a female preponderance (2:1), are arguably more common in the mandible when compared with maxilla and usually present with swelling of the retromolar trigone as the predominant symptom.⁷ The predominance of mandibular MECs, nevertheless, can also be attributed to the acceptability criteria of complete absence of antral extension for a maxillary lesion to qualify as a CMEC.

The origin of CMEC has long been a subject of controversy and multiple theories that have been proposed include the more likely possibility of (1) mucous cell metaplasia of odontogenic epithelium, as well as the possible origin from (2) ectopic salivary tissue trapped in bone either embrologically or iatrogenically, and (3) from the maxillary sinus epithelium.⁸ Eversole et al have attributed the origin of about 50% of all CMECs to the mucous cell differentiation in odontogenic epithelium, whereas according to Brookstone and Huvos, this percentage is close to 32%.^{8 9} There was absence of any salivary gland tissue or sinus epithelial rests in the present case and carcinomatous transformation from the odontogenic epithelium was confirmed after histopathological and IHC analysis of the sections of the surgical sample. The presence of mucous cells and consequential mucicarmine staining differentiates CMEC from the other histopathologically similar entities, notably, squamous odontogenic tumour, clear cell odontogenic tumour and primary intraosseous squamous cell carcinoma.

Strict radiological and histopathological diagnostic criteria have been proposed by Alexander et al¹⁰ and modified by Browand and Waldron.¹¹ Radiologically, the presence of an intact cortical plate along with bony expansion and destruction has previously been proposed as being mandatory for the diagnosis of CMEC, with the premise of ruling out lesional origin outside the jaw. However, as in our patient, a primary intraosseous tumour can still erode the cortical plate and this criteria can be disregarded as long as extra-osseous lesional origin is ruled out. In a case report, Waldron and Koh accepted cortical plate defects in the mandible overlying a radiolucent lesion if there was no obvious soft tissue lesion and the periosteum was intact.¹² A review of radiological features of CMECs by Chan et al is one of the very few articles focusing on the imaging aspects and stated the importance of (1) the presence of a well-defined sclerotic boundary, (2) internal amorphous sclerotic bone, (3) multiple small loculations with or without septae and (4) expansion and perforation of the outer cortex with surrounding soft tissue extension for the differential diagnosis,¹³ though diagnostic confirmation still requires clinical, histopathological and the IHC characteristics.

The histopathological criteria for diagnosing this rare entity includes microscopic confirmation of the diagnosis, positive mucin staining, exclusion of primary lesion in salivary gland and other odontogenic tumours.^{10 11} However, cognizance is required of the fact that intracellular mucin, although a confirmatory evidence, is not diagnostic of CMEC as the occurence of mucous cells in inflammatory and developmental odontogenic cysts is well documented (radicular cysts, 18.1%; dentigerous cysts, 23.8%; primordial cysts 26.9%).¹⁴

Patients present commonly with swelling over the retromolar trigone with or without pain. Long-standing lesions may have associated altered nerve sensations. The symptom in our patient was swelling, as was the case with most of the patients in the study by He et al.⁵ Based on the clinical staging proposed by Brookstone and Huvos, which is based on the condition of the overlying bone, we staged the patient as stage III. Lesions with intact cortex with no bone expansion are stage I; tumours with intact cortex but intrabony expansion are stage II; and stage III lesions are characterised by perforation of the cortex or nodal metastasis.⁹

Prognostication of CMECs has been challenging owing to the disparate treatment in the few reported cases. Tumours with cortical plate perforation, as in the case of our patient, are known to be associated with an aggressive clinical course. The most common site of metastases being regional lymph nodes (6%) with eight documented cases of regional spread. Distant metastases, although rare, have been reported in the lungs and brain with one case report of spread to the ipsilateral clavicle.¹⁵

The treatment of choice is en bloc resection for all of the three grades, along with segmental or hemimandibulectomy for advanced lesions. Brookstone and Huvos observed that surgical modalities short of an en bloc resection (enucleation, curettage, marginal resection) with or without adjuvant therapy resulted in a recurrence rate of 40%–45%, whereas in patients undergoing radical surgery with or without adjuvant therapy, only 4% recurred.⁹ The importance of radical surgery is also underscored by the high mortality rates in patients of CMEC with local recurrence and subsequent intracranial invasion.¹² In a report of 24 cases, He et al have stressed on the prognostic importance of radical surgery in view of the fact that one of four patients with positive margins died.⁵

Kochazi et al, in 2004, suggested a guideline for reporting case reports of CMEC, in view of the rarity of this entity and the consequent missing data. The underutilisation of radiotherapy as an adjunct was clearly documented with only 1% of the patients receiving resection and radiotherapy both. The lack of systematic data reporting for CMEC was also highlighted by the fact that over 72% of the case reports failed to provide specific information of the treatment received.¹⁶ Patients who received postoperative radiotherapy had a 5% benefit in the survival rate and thus radiotherapy should be recommended to improve the prognosis in patients with positive margins, node-positive disease, intermediate-grade and high-grade lesions.⁵ In view of our patient having cortical plate perforation with tumour present at the inked margin and an intermediate-grade CMEC, he was planned for adjuvant radiotherapy.

We have made an effort to include all the clinical, radiological, pathological and surgical aspects as advised by the guideline by Kochazi et al, as well as the immunohistochemistry employed and adjuvant treatment received by the patient.

In conclusion, though CMECs have an indolent natural course, they can be locally aggressive and thus warrant a wide en bloc resection with segmental mandibulectomy followed by careful assessment for adjuvant radiotherapy. Adjuvant radiotherapy has been shown to increase survival and improve prognosis in patients with intermediate-grade and high-grade tumours, positive margins and node-positive disease and should be strongly considered for this carefully selected high-risk subgroup.

Learning points.

• Central mucoepidermoid carcinoma is a rare entity with unique radiological, histopathological and immunohistochemical diagnostic criteria.

• Radical surgery, that is, en bloc resection, forms the mainstay of treatment as reflected by poorer survival in patients treated with less radical resections, that is, curettage, marginal resections.

• Adjuvant radiotherapy has been shown to increase local control and survival in patients with intermediate-grade and high-grade tumours, positive margins and node-positive disease and has a definite role in these subsets of patients.