Myoepithelial Carcinoma Ex Pleomorphic Adenoma of the Maxillary Sinus: A Case Report and Review of Literature

Abstract

Myoepithelial carcinoma ex pleomorphic adenoma is defined as a malignant epithelial neoplasm arising from a primary or recurrent benign pleomorphic adenoma. This type of tumor comprises 3.6% of all salivary gland tumors and 12% of malignant ones. Clinically, it most commonly presents as a firm mass in the parotid gland. The development of this neoplasm in the sinonasal and nasopharyngeal regions is extremely rare and only few cases are reported in the literature. The prognosis of myoepithelial carcinoma is variable. Marked cellular pleomorphism, high mitotic rate, and high proliferative activity correspond to a poor prognosis. In this article, the authors report the histopathological features of a clinical case of a 64-years-old patient with a large median maxillary neoplasm diagnosed as myoepithelial carcinoma/ex-pleomorphic adenoma. The tumor was resected and subjected to secondary reconstruction using a revascularized free fibula flap. The myoepithelial derivation of neoplastic cells was demonstrated by immunohistochemical positivity for S-100 protein (strong and diffuse), cytokeratin 14 (strong and diffuse), and GFAP (focal).

Introduction

Carcinoma ex pleomorphic adenoma (CXPA) is an epithelial and/or myoepithelial malignancy that develops from primary or recurrent pleomorphic adenoma (PA) and accounts for 3.6% of all salivary gland tumours [1].

Myoepithelial carcinoma (MC) is a neoplasm comprised almost exclusively of cells with myoepithelial differentiation and shows infiltrative growth and metastatic potential. Most cases arise in the parotid gland, but they also occur in submandibular and minor glands, usually in the palate, and rarely in the base of the tongue, maxillary sinus, and larynx [2].

In the maxillary sinus, rare cases of myoepithelial carcinoma have been published and only one where a background of pleomorphic adenoma has been demonstrated [3, 4].

We report a case of myoepithelial carcinoma ex pleomorphic adenoma in a patient who presented with a large median maxillary neoplasm.

Case Report

A 64-year-old patient presented to our service for evaluation and treatment of a large mass of the central face. The patient reported a previous surgery for removal of a pleomorphic adenoma at the same site. After primary objective examination, an incisional biopsy of the mass was performed and histopathologic examination resulted in a diagnosis of myoepithelial carcinoma ex-pleomorphic adenoma (Fig. 1a and b).

Fig. 1.

a Microscopic image of the previous pleomorphic adenoma diagnosed three years earlier (H&E, × 400). b Sections showing a residual component of pleomorphic adenoma on the border of tumor (H&E, × 200)

A computed tomography (CT) scan showed a wide, solid mass with focal necrosis that extended into the nasal cavities and maxillary sinuses. It resulted in both swelling and destruction of the bony skeleton. Inferior destruction of the hard palate was observed with extension into the oral cavity.

The patient underwent excision of the mass by a modified Weber Ferguson incision.

The surgical defect was reconstructed with a free fibula osseo-myocutaneous flap customized by rapid prototyping.

The gross specimen comprised a large, mucosa-surfaced mass (75 × 65 × 52 mm) that involved the full thickness of the hard palate, a portion of nasal septum, the maxillary sinuses, and the nasal cavities. The cut surface was grey-white with focal hemorrhage. Both hard and soft tissues were identified (Fig. 2a).

Fig. 2.

a Cut surface of the specimen after formalin fixation. b Histologically, sections show a tumor with infiltration into adjacent bone. Multiple nodules with hypercellular areas and myxoid stroma are seen (H&E, × 100)

Histologic examination revealed a neoplasm of disorganized, hypercellular nodules with pushing to infiltrative borders, extensive bone infiltration, and minimal oral mucosal involvement. The nodules comprised solid and sheet-like growths of polygonal epithelioid cells. A smaller component exhibited plasmacytoid features with abundant eosinophilic cytoplasmic inclusions. The tumor stroma was predominantly myxoid and positive for Alcian blue stain. Neoplastic cells showed moderate nuclear pleomorphism with conspicuous nucleoli, low mitotic rate, and abundant eosinophilic cytoplasm (Fig. 2b). The myoepithelial derivation of neoplastic cells was demonstrated by immunohistochemical positivity for S-100 protein (strong and diffuse), cytokeratin 14 (strong and diffuse), and GFAP (focal). The proliferative index (Ki-67/MIB1) was estimated at 10% (Fig. 3a–c). Areas morphologically consistent with remnants of the previous pleomorphic adenoma were observed focally.

Fig. 3.

a Microscopic examination showing sheets of polygonal cells with moderate amounts of cytoplasm and hyperchromatic nuclei with mild to moderate pleomorphism and inconspicuous nucleoli (H&E, × 400). b A smaller component exhibits plasmacytoid features with abundant eosinophilic cytoplasmic inclusions (H&E, × 400). c Immunohistochemical analysis shows strong and diffuse positivity for S-100 protein (× 400)

A diagnosis of low-grade myoepithelial carcinoma arising from pleomorphic adenoma was made. The resection margins were extensively sampled and found to be negative for tumor involvement. The tumor was staged as pT3. The patient did not need adjuvant radiation therapy. The patient was followed for four years without evidence of recurrence.

Discussion

The incidence of malignancy arising in PA is less than 2% for tumors that have been present for less than 5 years and 10% for those present for more than 15 years. In order to establish a diagnosis of CXPA, histologic evidence of a PA must be present [5]. Various studies suggest that radiation, genetic instability, and p16 protein over-expression for promotor methylation may all contribute to malignant transformation [6, 7]. A molecular study suggests a multistep model with the progressive loss of heterozygosity at chromosomal arms 8q, then 12q, and finally 17p [8, 9]. Genes involved in tumor suppression, cell cycle control, and growth are also involved: a point mutation of p53 was reported originally by Righi et al. [10, 11].

Clinically, CXPA most commonly presents as a firm mass in the parotid gland. This presentation can be mistaken for a PA; however, a rapid increase in size should raise suspicion for malignancy [12].

In a recent work, Wanpeng et al. conducted a retrospective analysis of 17 patients with PA and CXPA in the sinonasal and nasopharyngeal regions [13]. Ten patients were diagnosed with benign PA and seven patients were diagnosed with CXPA, including five cases of adenocarcinoma, one of mucoepidermoid carcinoma, and one of adenoid cystic carcinoma. In a review of the literature, the authors further reported 20 cases of CXPA in this region. In total, the subtypes of malignancy were as follows: adenoid cystic carcinoma (n = 12), adenocarcinoma NOS (n = 10), myoepithelial carcinoma (n = 1), squamous cell carcinoma (n = 1), mucoepidermoid carcinoma (n = 1), mucoepidermoid and squamous cell carcinoma (n = 1), and histologic subtype not reported (n = 1). We concluded that the adenoid cystic carcinoma subtype of CXPA is more common than the adenocarcinoma subtype in the nasopharynx and nasal regions. The other histologic subtypes, such as myoepithelial carcinoma, are extraordinarily rare in sinonasal and nasopharyngeal regions. Recently, it was observed that 66 (0.009%) out of 7190 salivary gland tumours showed maxillary sinus involvement, none of them diagnosed as myoepithelial carcinoma, confirming its rarity in this anatomic location [3, 14].

Myoepithelial carcinoma (MC) is characterized by nearly exclusive myoepithelial differentiation and evidence of malignancy, usually in the form of infiltration of surrounding tissues. Grossly, it is variable in size, grey-white and firm, and has cut surfaces showing areas of necrosis and cystic change. Tumors arising in the parotid are usually partially or completely encapsulated, while at other sites they may be unencapsulated. Histologically, MC may show various patterns including multinodularity, sheets, trabeculae, or nests, and the stroma may be myxoid or hyaline. The cellular morphology is most commonly epithelioid but may also be spindled, stellate, plasmacytoid, or clear cell. The histology may be low grade with mild pleomorphism, inconspicuous nucleoli, and fine chromatin, or high grade with nuclear enlargement, pleomorphism, hyperchromasia, prominent nucleoli, irregular nuclear membranes, and occasional tumor giant cells. Pleomorphism and mitotic activity is variable and cellular atypia may not be present in all cases, so infiltration into the adjacent tissue is the most reliable criteria for diagnosing malignancy [1–4]. Perineural invasion and vascular invasion are other features of malignancy; the former is seen in 44% of MCs and the latter in 16%. In one series, 40% of tumours were categorized as high-grade and 60% as low-grade [15].

To establish a diagnosis of MC, immunohistochemical reactivity for broad-spectrum cytokeratins and at least some of myoepithelial markers, including αSMA, GFAP, CD10, p63 protein, and calponin, is required [2]. All MCs display diffuse or patchy staining for S-100 protein and vimentin, and about half of cases are positive for CK14 and CK5/6 [16]. The Ki-67/ MIB1 proliferation index in one series was 35% (range 15–65%), with any count above 10% said to be diagnostic of malignancy in a myoepithelial neoplasm [17]. The differential diagnoses of MC encompass a wide variety of neoplasms including myoepithelioma, epithelial-myoepithelial carcinoma, clear cell adenocarcinoma, synovial sarcoma, malignant peripheral nerve sheath tumour, leiomyoma, plasmacytoma, malignant melanoma and many more owing to its morphologic heterogeneity [13].

Recent molecular genetic data suggest that EWSR1 gene rearrangement is a common event in myoepithelial tumours arising outside the salivary glands, regardless of anatomic location [18].

Our case comprised a large neoplasm of the anterior maxillary region that involved the hard palate, nasal septum and nasal cavities, in a patient with a previous surgery for PA three years prior. Histologically, the neoplasm was composed of hypercellular nodules and solid sheets, with a myxoid and hemorrhagic stroma, and background of residual PA. The neoplastic myoepithelial cells showed moderate nuclear atypia. Despite a lack of cellular pleomorphism or significantly high mitotic index, the extensive bony infiltration and the clinical features favored the diagnosis of a low-grade myoepithelial carcinoma rather than an hypercellular PA. To the best of our knowledge, in the maxillary sinus, only six cases of MC have been previously published and, to date, only one case arising in a background of PA [3, 4] [19–22]. Of these, three occurred in males and three in females. The ages ranged from 38 to 67 years. The clinicopathologic features of all cases, including our case report, are summarized in Table 1.

Table 1.

Clinical-pathological features of all MCs described in the maxillary sinus available in the scientific literature

ID	Year of publication	Sex of patient	Age of patient	Tumoral dimension (mm)	Laterality	Histology	Therapy	Prognosis
Case 1(24)	1998	M	67	60 × 50x40	Right	Low grade	Surgery (RM)	NA
Case 2(25)	2000	M	38	55	NA	Clear cell Low grade	Surgery (RM) Chemo	DOD (72 months)
Case 3(26)	2008	F	41	NA	Left	NS	Surgery (RM) Chemo-radiation	DOD (13 months)
Case 4(27)	2009	F	47	40 × 30x30	Left	NS	Surgery (PM) Radiation (ALR)	AW (30 months)
Case 5(4)	2013	F	39	50 × 25x20 (R) 60 × 55x25 (L)	Bilateral	History of PA LVI	Surgery (PM)	NA
Case 6(3)	2019	M	44	NA	Left	Rhabdoid features	Surgery (NS)	Lost to FU
Present case	2020	M	64	75 × 65x52	Bilateral	Low grade	Surgery (RM)	AW (65 months)

MCs myoepithelial carcinomas, M male, F female, R right, L left, NA not available, NS not specified, PA pleomorphic adenoma, LVI linfovascular invasion; RM radical maxillectomy, PM partial maxillectomy, ALR After local recurrence, DOD death of disease; AW alive and well, FU follow-up

MC arising in PA may be an under reported tumor, probably due to difficulty in diagnosing the myoepithelial component in the absence of marked cytological atypia, mitoses or necrosis, and the inconspicuous nature of the coexisting PA [4]. Accurate distinction between HG-CXPA, LG-CXPA, and PA is important because the prognosis and treatment vary between these entities. PA is a benign neoplasm and complete surgical resection is associated with excellent prognosis. HG-CXPA is usually associated with a dismal prognosis and adjuvant therapy, such as carbon ion radiotherapy, is often necessary. Compared to PA, LG-CXPA is associated with increased local recurrence, and neoadjuvant therapy is applied to a subset of patients, depending on the histopathologic findings and tumor stage [23]. Evidence of a pre-existing PA at the same site may be crucial in achieving an accurate diagnosis which is essential for optimal management. According to some authors, MC arising de novo may be more aggressive tumours as compared to those arising in recurrent PA [4].

Overall, the prognosis of MC is variable. Marked cellular pleomorphism, high mitotic rate, and high proliferative activity correlate with poor prognosis. Approximately one third of patients die of disease, another third have multiple recurrences, and another third remain disease-free [1, 2].

Conclusions

Myoepithelial carcinoma of maxillary-nasal region is extraordinarily rare and poorly characterized; thus far, only one tumor is described arising from pleomorphic adenoma at this site. As seen in this case, these tumors may extensively invade bone and the respiratory tract with functional and esthetic consequences. Correct histopathologic diagnosis and adequate primary excision of the lesion are essential to ensure primary prevention of these malignancies.

Funding

The authors have no funding, financial relationships.

Compliance with Ethical Standards

Conflict of interest

The authors have no conflicts of interest to disclose.

Ethical Approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki declaration of 1975.

Informed Consent

Informed consent was obtained from patient for being included in the study.