Pleomorphic Adenoma

Pleomorphic Adenoma

A benign salivary gland neoplasm (the “benign mixed tumour”), characterised microscopically by an unusually broad range of tissue types arising from both epithelial (ductal) and myoepithelial cells, with a variable mesenchymal stroma. It is the most common benign neoplasm of both the major and minor salivary glands.

Etiology and Pathophysiology

Contributory factors :

• Aetiology is unknown.
• Cause of most lesions is a chromosomal translocation activating one of two genes, PLAG1 or HMGA2 (transcription factors important in normal development); their constitutive activation drives cell proliferation and abnormal differentiation, explaining the varied tissues formed.
• Additional chromosomal abnormalities (oncogenes, tumour suppressor genes) accumulate with time and probably account for the risk of malignant transformation in longstanding tumours.
• Incidence has been reported to increase 15–20 years after exposure to radiation.

Prevalence

• Most common benign neoplasm of both major and minor salivary glands; accounts for up to ~80% of benign salivary gland tumours and ~75% of parotid tumours.
• Wide age range (children and adults), but most common in the 3rd–6th decades / middle age (mean age ~40 years).
• Female predominance (~2:1).
• Incidence in major vs minor salivary glands is roughly 10:1.

Histological Features

• Arises from two cell types — epithelial (ductal/intercalated duct) cells and myoepithelial cells — accounting for the obsolete term “mixed tumour.”
• Each lesion is circumscribed with a capsule around most of the periphery, but the capsule is variable and almost never complete; finger-like extensions (pseudopods) bulge into and beyond the capsule.
• Bosselated outer surface with tongue-like protrusions (pseudopods).
• Epithelial (ductal) component: forms ducts, small cysts, sheets and strands of dark-staining cells; inner layer of cysts/tubules.
• Myoepithelial component: outer layer of cysts/tubules and scattered in the stroma; cytology may be plasmacytoid, spindled, epithelioid, clear or stellate.
• Stromal component: highly variable — myxoid, chondroid (cartilage-like) or myxochondroid; may be hyalinised or densely collagenous, and cartilage may ossify to form bone.
• Cells at the periphery of epithelial sheets detach and secrete matrix proteoglycans, forming the dispersed “myxoid” stroma.
• Proportion of epithelial/myoepithelial cells vs stroma gives cell-rich or stroma-rich types; stroma-rich lesions are more prone to recurrence and more common in the parotid.
• Metaplastic changes may include adipose, osseous, squamous (sometimes keratinising), sebaceous and mucinous metaplasia; occasional foci of keratin formation.
• Intravascular permeation reported in a small percentage of cases and does not increase recurrence or metastasis risk.

Clinical Features

Location

• Major glands: most common site is the superficial lobe of the parotid gland; less commonly the submandibular and sublingual glands.
• Minor glands: most common at the palate and upper lip; can occur at any oral site and also nose, paranasal sinuses and larynx.
• ~75% of parotid tumours are pleomorphic adenomas; ~20% are distributed roughly equally between submandibular gland and intraoral minor glands (usually palate).

Appearance

• Slow-growing, painless submucosal mass; may remain undiagnosed for years (often takes several years to reach ~2 cm; most parotid lesions 2–6 cm, giant lesions reported).
• Smooth-surfaced, dome-shaped, rubbery/firm mass on palpation; smooth when small but often lobulated when large.
• Overlying skin or mucosa is mobile over the lump; in the palate the inflexible mucoperiosteum may appear fixed.
• May be fixed or mobile.
• Symptoms depend on site and may include pain, facial nerve palsy, skin fixation and epistaxis.
• Warning sign: rapid enlargement of a tumour nodule should raise suspicion of malignant transformation.

Differential Diagnoses

• Other benign salivary neoplasms: Warthin’s tumour, oncocytoma, basal cell adenoma, canalicular adenoma, myoepithelioma.
• Low-grade malignant salivary neoplasms (e.g. mucoepidermoid carcinoma, adenoid cystic carcinoma) — clinical appearance is not specific and can mimic a benign mass.
• Carcinoma ex pleomorphic adenoma (suspect with rapid growth, pain, facial nerve palsy, or skin fixation in a longstanding lesion).
• Enlarged intraparotid lymph node (best differentiated from neoplasm by ultrasound).
• For a minor-gland/upper-lip lump, malignancy should be considered until proven otherwise.

Relevant Clinical Investigations

• History and clinical examination (including head and neck exam).
• Fine needle aspiration (FNA): key investigation; almost always gives the correct diagnosis for pleomorphic adenoma. Small incisional biopsies or FNA may not be representative of the entire lesion and can complicate diagnosis.
• Imaging: MRI is preferred (detects perineural spread and base-of-skull invasion); ultrasound (with guidance for deeper lesions) differentiates neoplasm from intraparotid lymph node; CT/CBCT to detect palatal bone perforation. Ultrasound and ultrasound-guided FNA used for major-gland lesions.
• Sialography no longer has a role in investigating salivary neoplasms.
• Histological confirmation of disease is required.

Patient Management

• Treatment: excision of the tumour with a margin of normal tissue (intact removal); the lesion is encapsulated but must not be enucleated.
  • Superficial parotid lesions: removal of the whole superficial lobe (superficial parotidectomy); deep-lobe tumours require complete parotidectomy.
  • Submandibular lesions: whole gland removed.
  • Minor-gland/intraoral lesions: excised with a few millimetres of normal margin; recurrence rate very low.
• Recurrence factors: incomplete encapsulation, extracapsular extension, and intra-operative rupture/spillage (myxoid contents can seed multifocal recurrence, especially in the parotid). Recurrence, when it develops, is often multifocal and difficult to eradicate.
• Surgical risks (parotidectomy): facial nerve damage, Frey’s syndrome, haematoma.
• Prognosis: excellent after complete surgical resection in most cases.
• Malignant transformation: longstanding lesions may transform to carcinoma ex pleomorphic adenoma (reported in up to ~5–7% of cases), which is aggressive with a poor prognosis — warranting timely excision and follow-up.