Definition

A malignant epithelial tumour characterized by cytologic uniformity, morphologic diversity, an infiltrative growth pattern, and low metastatic potential.

 ICD-O code 8525/3

Synonyms Terminal duct carcinoma, lobular carcinoma

Epidemiology

PLGA is the second most common intraoral malignant salivary gland tumour, accounting for 26% of all carcinomas {2711}. The female-to-male ratio is about 2:1. Patient age ranges from 16-94 years mean 59 years. Over 70% of the patients are between the ages of 50 and 70 years {342,697}. To date, only two tumours have been reported in the pediatric population {2641}.

 Localization

Approximately 60% of the cases have involved the palate. Other intraoral locations are the buccal mucosa, retromolar region, upper lip, and the base of the tongue {342,697}. Uncommon locations include major salivary and lacrimal glands, nasopharynx and nasal cavity {1299,2763}.

Clinical features

A painless mass in the palate is the most common clinical sign. The duration of the lesion has varied from weeks to as much as 40 years {342}. Bleeding, telangiectasia, or ulceration of the overlying mucosa occurs occasionally.

Macroscopy

PLGA usually appears as a firm, circumscribed, but non-encapsulated, yellowtan lobulated nodule up to several centimetres in greatest dimension (average 2.2 cm) {342}.

Histopathology

PLGA is characterized by cytologic uniformity, histologic diversity, and an infiltrative growth pattern. The tumour cells are small to medium size and uniform in shape with bland, minimally hyperchromatic, oval nuclei and only occasional nucleoli. Mitoses are uncommon and necrosis is not typical. The striking feature of these carcinomas is the variety of morphologic configurations between tumours and within an individual tumour. The main microscopic patterns are: 1) lobular, 2) papillary or papillary-cystic (typically focal), 3) cribriform areas sometimes resembling those in adenoid cystic carcinoma, and 4) trabecular or small, duct-like structures lined by a single layer of cuboidal cells. The cells form concentric whorls or targetoid arrangements around blood vessels or nerves. Foci of oncocytic, clear, squamous or mucous cells may be found. Stroma may show areas of mucinosis or hyalinization. Despite the innocuous cytologic appearance, the neoplasm always invades adjacent soft tissues and is uncapsulated. Neurotropism is common in PLGA. Invasion of adjacent bone may be seen in tumours of the palate or mandible.

Immunohistochemistry

 The neoplastic cells of PLGA are immunoreactive with antibodies to cytokeratin (100%), vimentin (100%), S-100 protein (97%), carcinoembryonic antigen (54%), glial fibrillary acidic protein (GFAP) (15%), muscle specific actin (13%), and epithelial membrane antigen (12%) {342,2011,2763}. Expression of galectin 3 has been reported to be significant in PLGA {2006}. Bcl-2 is over expressed in most cases of PLGA {342,2011}.

 Differential diagnosis

The differential diagnosis includes pleomorphic adenoma (PA) and adenoid cystic carcinoma (AdCC), especially in small biopsy specimens. Unlike PLGA, PA is nearly always circumscribed and is composed of proliferating stromal, epithelial, and myoepithelial cells. It lacks the infiltrative, noncircumscribed character of PLGA. Although myxoid tissue is present in both tumours, the myxochondroid and chondroid areas present in PA are not evident in PLGA. Also, the typical benign plasmacytoid myoepithelial cells characteristic of palatal PA are seldom observed in PLGA. Staining with GFAP may be helpful in differentiating PA from PLGA. The distinction between PLGA and AdCC is based primarily on cytologic features. Cells in PLGA are cuboidal or columnar. They have vesicular nuclei and often conspicuous eosinophilic cytoplasm without the basaloid features characteristic of AdCC. Papillary and fascicular growth patterns are extremely rare in AdCC. Furthermore, PLGA does not have large cribriform pseudocystic spaces that contain pools of haematoxyphilic glycosaminoglycans. The solid cellular areas of PLGA lack nuclear pleomorphism, necrosis, increased mitotic activity, and the numerous tubular structures characteristic of the solid variant of AdCC. The potential discriminating value of immunohistochemistry between cases of PLGA and AdCC remains controversial {547}, although some subtle differences may be apparent when series of these two neoplasms are studied {342,2006,2011,2391}. Proliferative cell marker rates in PLGA are usually less than 6.4% (mean values 1.6% and 2.4%) {2391}. However, a higher proliferative rate (average 7%) has been reported by others investigators {2011}.

Genetics

 Cytogenetic studies of this tumour are few. A total of 7 cases of which two were carcinoma ex-pleomorphic adenoma, have been reported. Alterations at 8q12 were found in two, 12q rearrangements in five, two showed a clonal t(6:9) (p21;p22) and one a monosomy 22 {1651}. Cytogenetic alterations in PLGA have frequently displayed chromosome 12 abnormalities affecting the q arm and the p arm {1651}. 

Prognosis and predictive factors

 The overall survival rate of patients with PLGA is excellent {164,342,696, 697,808}. A review of series with large numbers of cases and with long-term follow- up revealed a local recurrence rate between 9% and 17% and a regional metastases rate from 9-15% {342,697}. Distant metastases have seldom been reported {342,697}. Deaths attributed to tumour are unusual, and they occurred after prolonged periods {342,697}. In studies which accepted tumours with a predominant papillary configuration a higher incidence of cervical lymph node metastasis was reported {697}. The status of such tumours within the spectrum of PLGA is controversial. Dedifferentiation of PLGA has been reported and carries a less favourable prognosis. Such tumours should not be included under the rubric of typical PLGA {2368}. Treatment consists of complete surgical excision. Neck dissection should be added for those patients with cervical adenopathy.

Cribriform adenocarcinoma of the tongue

A possible variant is cribriform adenocarcinoma of the tongue, but it is not yet clear whether this represents a genuine entity or just an unusual growth pattern in PLGA, with which there appears to be some overlap {1718}. So far described only in one series, all cases presented with a mass in the tongue, usually the posterior part, and synchronous metastases in lateral neck lymph nodes, but no distant spread. There was an equal sex incidence and the mean age at presentation was 50.4 years (range 25-70). The tumour grows beneath the surface epithelium and infiltrates soft tissue. It is divided by fibrous septa into lobules, which are solid or cribriform. A characteristic feature is that some nearly solid islands have a glomeruloid arrangement of broad microfollicular papillae separated from a layer of peripheral columnar cells by a narrow cleft. Small numbers of tubules are seen, and occasional spindling of tumour cells may occur. The nuclei are uniform, pale and often overlap, closely mimicking those of papillary carcinoma of the thyroid. Mitotic figures are sparse. No necrosis or significant haemorrhage is seen, and the stroma includes hyalinized areas, and rarely psammoma bodies. The tumours are positive for cytokeratin, and more patchily for S-100 protein. Myoepithelial markers, such as actin are either negative or only focally positive. Thyroglobulin staining is consistently negative.