Adenoid Cystic Carcinoma of Salivary Gland

Adenoid cystic carcinoma (ACC) of the salivary gland is a slow growing but relentlessly invasive malignant tumour that accounts for 10 percent of salivary gland cancers and about 25 percent of minor salivary gland cancers. It arises in the minor glands of the palate, in the submandibular and sublingual glands, and in the parotid. It affects adults aged 40 to 60 years, with a slight female predominance.

The tumour consists of basaloid epithelial and myoepithelial cells in cribriform (Swiss cheese), tubular, or solid patterns. A MYB-NFIB fusion occurs in about 60 to 80 percent. Its hallmark is perineural invasion (in more than 50 percent), leading to pain, nerve palsy, and spread along cranial nerves (V and VII) to the skull base.

Lymph node metastasis is uncommon (5 to 15 percent), but haematogenous metastasis to the lung, bone and liver occurs in 40 to 50 percent, often years later. The 5-year survival is 70 to 90 percent, but this falls to 20 to 40 percent at 15 to 20 years because of late recurrence and metastasis, so ACC is a disease with long natural history. Solid pattern carries the worst outcome.

• Slowly enlarging, firm, painless or painful mass in the palate, parotid, submandibular region, tongue, or paranasal sinus; pain is out of proportion to size owing to perineural invasion.
• Facial nerve palsy (parotid), numbness or paraesthesia in the distribution of V2 or V3, tongue weakness (hypoglossal), trismus.
• Palatal tumour: submucosal nodule with overlying ulceration, loose teeth, nasal obstruction, epistaxis.
• Sinonasal tumour: nasal obstruction, proptosis, diplopia.
• Lung metastases: usually asymptomatic for years; cough, haemoptysis, dyspnoea when extensive.
• Red flags: facial nerve weakness, cranial neuropathy, skull base pain, new bone pain, and respiratory symptoms.

• Clinical examination of the oral cavity and cranial nerves; palpation of nodes.
• Incisional or core needle biopsy: cribriform, tubular or solid growth of basaloid cells with hyaline stroma and perineural invasion; immunohistochemistry (CD117, p63, SMA, SOX10) and MYB or MYB-NFIB fusion testing by FISH or RT-PCR for confirmation.
• MRI with contrast and fat suppression: infiltrative mass with perineural spread along the foramina (enlarged enhancing nerve, expanded foramen ovale or stylomastoid foramen); CT for bony destruction.
• Staging with CT chest (and PET-CT for baseline) to detect pulmonary nodules; bone scan or liver imaging if symptomatic.
• Exclude pleomorphic adenoma, basal cell adenocarcinoma, polymorphous adenocarcinoma, mucoepidermoid carcinoma, squamous cell carcinoma, and metastasis.

• Surgery with wide margins is the primary treatment: wide local excision (palate: partial maxillectomy), total parotidectomy with sacrifice of the facial nerve when infiltrated (with nerve grafting using sural or great auricular nerve), submandibular gland excision with neck dissection of level I when needed; frozen section of the proximal nerve to ensure clear perineural margins.
• Neck dissection only for clinically positive nodes (node metastasis is uncommon).
• Adjuvant radiotherapy 60 to 66 Gy in 30 to 33 fractions (up to 70 Gy for gross residual disease), given to almost all patients because of the high local recurrence risk with perineural invasion, close or positive margins, or advanced stage, covering the skull base along the involved nerve; neutron or carbon ion radiotherapy is used in specialist centres for unresectable disease.
• Concurrent cisplatin 40 mg/m2 intravenously weekly for 6 weeks for positive margins or unresectable disease, with pre-hydration, antiemetics (ondansetron 8 mg), and monitoring of renal function, magnesium and hearing.
• Metastatic disease: indolent lung metastases can be observed for years; resection of oligometastases; systemic therapy for symptomatic progressive disease: cisplatin 50 mg/m2 on day 1 with doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days for up to 6 cycles, or vinorelbine 25 mg/m2 days 1 and 8 with cisplatin 80 mg/m2, or lenvatinib 24 mg orally once daily (dose reduced for toxicity; monitor blood pressure, proteinuria, and thyroid function), or axitinib 5 mg orally twice daily; response rates are 10 to 30 percent.
• Pain: neuropathic agents (gabapentin 300 mg at night increased to 600 mg three times daily; amitriptyline 10 to 25 mg at night) and opioids; palliative radiotherapy for bone metastases (8 Gy in a single fraction).
• Perioperative: cefazolin 1 g intravenously at induction; dental assessment and extraction before radiotherapy, with fluoride trays.
• Follow up: clinical review every 3 months for 2 years, every 6 months to 5 years, and then yearly for life; MRI of the primary and skull base at 3 to 6 months post-treatment and yearly for 5 years; CT chest every 6 to 12 months for at least 10 years.
• Counselling: slow disease course and late recurrences; long term follow up is essential.