Nasopharyngeal Pleomorphic Adenoma Progressing to Carcinoma ex Pleomorphic Adenoma with Metastases: A Case Report

Introduction

Salivary gland tumours are rare among head and neck neoplasms. Pleomorphic adenoma (PA), also known as a benign mixed tumour, is the most common primary salivary gland epithelial neoplasm. Although hormones and radiation exposure are suggested as risk factors, the etiology remains unconfirmed [1]. Most commonly, PA arises in the parotid gland, followed by the submandibular gland [1]. Tumours originating from the minor salivary glands are relatively uncommon, accounting for approximately 10–25% of all salivary gland tumours [2]. Among these, PA — also referred to as a benign mixed tumour — represents the most frequent histological subtype, constituting approximately 65% of all salivary gland tumours and nearly 40% of those arising from minor salivary glands [3]. If it originates from minor salivary glands, the palate is the most frequent site, but it may also occur in the trachea, larynx, sinuses, upper lip, or cheek [3]. Its occurrence in the nasopharynx is rare, with only 22 cases reported. Histogenesis of pleomorphic adenomas (PAs) in unusual sites, such as the nasal cavity, pharynx, jaw, or lymph nodes, likely arises from heterotopy of minor salivary glands. Patients with minor salivary gland PA typically present in the fourth to sixth decades of life [4], with a slight female predominance [5]. Clinical presentation may include unilateral nasal obstruction, epistaxis, nasal swelling, an intranasal mass, and mucopurulent rhinorrhea [6].

The malignant transformation rate of PA is not precisely established, as many carcinomas ex pleomorphic adenomas (CXPAs) present without prior clinical history of PA. Progression to malignancy in recurrent PAs is very infrequent (the rate is around 3%) [1]. Known risk factors include older age, recurrent disease, radiation exposure, submandibular location, large tumour size, prominent hyalinization, and high mitotic activity. Clinically, carcinoma ex pleomorphic adenoma (CXPA) may present with pain, ulceration, or nerve palsy. 

Case presentation

A 60-year-old man presented with right upper jaw pain, facial numbness, and weight loss of eight kilograms over four weeks and cervical lymphadenopathy, progressively worsening over six weeks. He had attended the emergency department with severe right-sided headache, oral pain, facial paraesthesia, fatigue, and further weight loss. His symptoms began in late December. He had previously been treated with antibiotics by a dentist for presumed dental infection. He reported photophobia, and his partner noted confusion.

Magnetic resonance imaging (MRI) showed a large, locally invasive tumour centred on the right maxilla and floor of the maxillary sinus, with bony destruction and soft tissue extension into the masticator space, pterygopalatine fossa, nasal cavity, and inferior orbital wall (Figure 1). There was perineural spread and significant lymphadenopathy in the right masticator space. Differential diagnosis included advanced squamous cell carcinoma of the right maxilla or, less likely, primary nasopharyngeal carcinoma.

Axial MRI of the head showing a large tumor centered on the right maxilla with local invasion 

A positron emission tomography–computed tomography (PET-CT) scan revealed an extensive right-sided mass involving the maxillary sinus with osseous destruction, pterygoid involvement, and extension to the parapharyngeal space. Superiorly, it extended to the foramen ovale and abutted the cavernous sinus. Right neck nodes at levels IB and II were involved, alongside bulky mediastinal nodes. Numerous pulmonary, hepatic, and osseous metastases were identified, including at the C7 vertebra.

Histopathological examination of a nasopharyngeal biopsy revealed fragments of pleomorphic adenoma with cartilaginous stroma and benign epithelial elements, without atypia (Figures 2-3). Fine-needle aspiration of a right level II cervical lymph node demonstrated malignant cells with high nuclear-to-cytoplasmic ratios, nuclear irregularities, and macronucleoli (Figure 4). That lymph node was excised, and histology performed (figures 5 and 6) Immunohistochemistry showed positivity of the tumour cells with broad-spectrum cytokeratin, GATA3, HER2 (3+ membranous staining) and androgen receptor (Figure 6). P40 and p16 stains were negative. These findings were consistent with metastatic carcinoma, likely CXPA.

Fluorescence in situ hybridization (FISH) demonstrated PLAG1 gene rearrangements (Figure 7) in both the benign nasopharyngeal PA and the metastatic carcinoma in the lymph node, confirming a diagnosis of CXPA.

FISH demonstrating Cytotest PLAG1 dual-colour break-apart probe

Discussion

CXPA is rare in major salivary glands and extremely uncommon in the nasopharynx. To our knowledge, this is the first reported case of nasopharyngeal PA progressing to CXPA with both nodal and distant metastases. Diagnosis was challenging, as the initial biopsy revealed only benign PA, while radiology strongly suggested an aggressive malignancy. This discrepancy prompted molecular analysis, where PLAG1 rearrangement proved essential in confirming the link between the primary PA and metastatic carcinoma.

The oncogenic role of PLAG1 in PA is well established. Initial cytogenetic studies revealed chromosomal translocations in approximately 70% of PAs [7, 8, 9, 10]. Further molecular investigations identified two primary target genes involved in these translocations: PLAG1 [11, 12], located at 8q12, in approximately 39% of cases, and HMGA2 [13], located at 12q14–15, in about 8%. The remaining 23% of karyotypically abnormal PAs exhibited a range of sporadic clonal chromosomal aberrations [14].

Metastatic CXPA remains poorly understood, with mechanisms likely involving genomic instability and subclonal progression. In this case, rapid dissemination with pulmonary involvement illustrates the potential aggressiveness of nasopharyngeal CXPA, possibly differing from salivary gland counterparts.

Human Epidermal Growth Factor Receptor 2 (HER2) overexpression or gene amplification is implicated in the pathogenesis of several epithelial malignancies, including breast, gastric, and salivary gland carcinomas. In carcinoma ex pleomorphic adenoma (CXPA), HER2 dysregulation is increasingly recognized as a driver of malignant transformation through activation of downstream signaling cascades such as PI3K/AKT and MAPK, leading to increased proliferation, survival, and metastatic potential [15]. HER2 gene mutation was likely a contributing factor in this particular case.

Strong HER2 and androgen receptor positivity offer potential modalities for treatment [16]. Unfortunately, in this case the disease progressed too rapidly for medical oncology to be useful.

The distinctive features of this case are the nasopharyngeal origin of PA, its progression to malignancy with metastases, and the use of FISH to genetically confirm the link between primary and metastatic sites. This case highlights the importance of correlating imaging, histology, cytology, and molecular studies in rare tumours. Ancillary testing such as FISH may be critical for accurate diagnosis when routine histology is inconclusive. 

Conclusion

We present the first case in the literature of nasopharyngeal pleomorphic adenoma transforming to carcinoma ex pleomorphic adenoma (CXPA) and producing with both regional nodal and distant metastases. We have utilised FISH for PLAG1 rearrangement in establishing the link between the primary site and metastasis, highlighting the diagnostic value of that auxiliary test. This case demonstrates the importance of considering CXPA in differential diagnoses of nasopharyngeal tumours and metastases of unknown origin. Regional metastasis of an apparent nasopharyngeal primary could represent CXPA; therefore, FISH could be used to rule out that possibility.

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