Definition

Adenoid cystic carcinoma is a basaloid tumour consisting of epithelial and myoepithelial cells in variable morphologic configurations, including tubular, cribriform and solid patterns. It has a relentless clinical course and usually a fatal outcome.

 ICD code 8200/3

 Epidemiology

Adenoid cystic carcinomas (AdCC) comprise approximately 10% of all epithelial salivary neoplasms and most frequently involve the parotid, submandibular and minor salivary glands. They comprise 30% of epithelial minor salivary gland tumours with the highest frequency in the palate, followed by the tongue, buccal mucosa, lip and floor of mouth. The tumour occurs in all age groups with a high frequency in middle-aged and older patients. There is no apparent sex predilection except for a high incidence in women with submandibular tumours {1663,1849,2016,2444}.

Clinical features

The most common symptom is a slow growing mass followed by pain due to the propensity of these tumours for perineural invasion. Facial nerve paralysis may also occur {1849,2016,2444,2519}.

Macroscopy

The carcinomas are solid, well-circumscribed but unencapsulated. They present as light-tan and firm masses of variable sizes. They are invariably infiltrative {161,1663,2439}.

Histopathology

 Tumours consist of two main cell types: ductal and modified myoepithelial cells that typically have hyperchromatic, angular nuclei and frequently clear cytoplasm. There are three defined patterns: tubular, cribriform and solid. In the tubular form, well-formed ducts and tubules with central lumina are lined by inner epithelial and outer myoepithelial cells. The cribriform pattern, the most frequent, is characterized by nests of cells with cylindromatous microcystic spaces. These are filled with hyaline or basophilic mucoid material. The solid or basaloid type is formed of sheets of uniform basaloid cells lacking tubular or microcystic formation. In the cribriform and solid variants small true ducts are invariably present but may not be immediately apparent. Each of these forms can be observed as the dominant component or more commonly as a part of a composite tumour {161,1663,1849,2016,2444, 2519}. The stroma within the tumour is generally hyalinized and may manifest mucinous or myxoid features. In some tumours there is extensive stromal hyalinization with attenuation of the epithelial component. Perineural and to a lesser extent, intraneural invasion is a common and frequently conspicuous feature of AdCC. Tumours can extend along nerves for a considerable distance beyond the clinically apparent boundaries of the tumour. In addition, the tumour may invade bone extensively before there is   radiographical evidence of osseous destruction. Adenoid cystic carcinoma occasionally occurs with other different neoplasms (hybrid tumours) {505,1823,2297,2416}. Pleomorphic carcinomas and sarcomatoid transformation of adenoid cystic carcinoma have been reported, mostly in recurrent and metastatic disease {397, 418}. Immunohistochemistry In differentiating between polymorphous low-grade adenocarcinoma and adenoid cystic carcinoma, Ki-67 immunostaining may be helpful {2680}. DNA content, C-kit and E-cadherin have been found to be associated with the biological behaviour of these tumours {636, 637,1215,1577}. Ki-67 and p53 have also been studied in these tumours {2844}, but no clear association with outcome have been reported. C-kit overexpression and its biological implication remains unknown. None of these markers, however, have been validated. Estrogen and progesterone receptor positivity has been reported in adenoid cystic carcinoma but the biological significance is currently unknown.

 Differential diagnosis

Pleomorphic adenoma, polymorphous low-grade adenocarcinoma, epithelialmyoepithelial carcinoma, basal cell adenoma or adenocarcinoma and basaloid squamous carcinomas are the major entities to be differentiated from adenoid cystic carcinoma.

Genetics

 Cytogenetics The most consistent, although not exclusive, reported alterations have been at chromosomes 6q, 9p and 17p12-13 regions. The t(6;9) (q21-24;p13-23) has been reported in several tumours and is considered to be a primary event in at least a subset of these tumours {657, 1220,1906,2238}. Molecular genetics Frequent losses at 12q (33%) 6q23-qter, 13q21-q22 and 19q regions (40%) have been reported {657}. A study of the 9p21 regions and the p16 gene found only one tumour with LOH at this region and no mutations of the gene {351}. A recent study of 25 tumours found a high frequency of LOH at 6q 23-25 and this alteration correlated with histologic grade and clinical behaviour {2098,2458). A recent genomic study identified new markers that may be helpful in future investigation of these tumours. Promoter methylation of the p16 was found in 20% of these tumours {1653}. Studies of other genes have been equally non-conclusive. Alterations of the p53 and Rb genes have been reported but no alterations in the K-ras have been found {2843}.

Prognosis and predictive factors

Factors that influence survival include histologic patterns, tumour site, clinical stage, bone involvement and status of surgical margins {1849,2016,2439,2444, 2519}. Generally, tumours composed of tubular and cribriform patterns pursue a less aggressive course than those with greater than 30% of solid component {2519}. Along with the histologic pattern, clinical stage greatly affects prognosis. Other studies have failed to confirm the value of grading {2439,2444} and underscored the significance of tumour size and clinical stage as the most consistent predictors of clinical outcome in patients with these tumours {2442,2449}. The 5- year survival rate is approximately 35% but the long-term survival is poorer. Eighty to 90% of patients die of disease in 10-15 years {993,2016}. The local recurrence rate ranges from 16-85% in several series of these tumours. Recurrence is a serious sign of incurability. Lymph node involvement is uncommon but has been reported to range from 5-25% and typically from tumours of the submandibular gland and is often due to contiguous spread rather than metastasis. The incidence of distant metastasis is estimated to range from 25-55%. The lung followed by bone, brain and liver are the common sites. Only 20% of patients with distant metastasis survive 5-years. The influence of perineural invasion on survival has been contradictory {860}. Wide local and radical surgical excisions with and without post-operative radiation is the treatment of choice {54,339, 1849,2439,2444,2519}. Radiation alone or with chemotherapy in the treatment of recurrent or metastatic disease has shown limited success. Radiotherapy, however, has been shown to improve local control in cases with microscopic residual disease {2670}. The value of chemotherapy in these tumours is limited and remains to be proven. Tumours of the salivary glands