Definition

 Large cell carcinomas are rare, highgrade malignant salivary gland epithelial tumours composed of pleomorphic cells with abundant cytoplasm and absence of features of other specific tumour types.

ICD-O code 8012/3

 Synonym

Large cell undifferentiated carcinoma.

 Epidemiology

Large cell carcinomas are exceptionally rare {1151,1816}. In the majority of cases, the patients were older than 60 years. Males and females are affected equally.

 Localization

 The majority of large cell carcinomas arise in the major salivary glands, especially the parotid gland {1151,1432,1768, 1816,1828,2836}. A few tumours of minor salivary gland origin have been reported {1768}.

 Clinical features

 Many patients present with a rapidly growing firm mass that often is fixed to adjacent tissue. Facial nerve paralysis and cervical lymph node enlargement are common findings.

Macroscopy

A large cell carcinoma is usually a poorly circumscribed, solid tumour with greyish white or tan cut surface. Necrosis and haemorrhage are easily found. Invasion into the adipose and muscular tissue adjacent to the salivary gland is common.

Histopathology

The tumour is composed of large, pleomorphic cells (>30μm) with an abundance of eosinophilic or occasionally clear, cytoplasm. In some tumours there is striking dyscohesive architecture resembling lymphoma. The tumour cell nuclei have a polygonal or fusiform shape, prominent nucleoli, and coarse chromatin with a vesicular distribution. Cell borders are usually well-defined. Bizarre giant tumour cells may be present. Mitotic figures are readily identified. The tumour growth pattern consists of sheets and trabeculae, with a conspicuous tendency for necrosis. Organoid, rosette-like, and peripheral palisading patterns characterize some of the large cell carcinomas {1828}. Rare foci of ductal or squamous differentiation can be present in large cell carcinomas. Lymphoid cell infiltration is usually focal and patchy. Perineural and vascular involvement is prominent.

Immunoprofile

Some cases of large cell carcinoma may be positive for one of the neuroendocrine markers, including chromogranin A, synaptophysin, CD57 (Leu-7), PGP9.5, or CD56 (neural cell-adhesion molecule). No immunoreactivity for cytokeratin 20 was found. The Ki-67 (MIB-1) labeling index is high and often greater than 50%. In two reported cases, the tumour cells showed diffuse immunoexpression of bcl-2 protein, epidermal growth factor receptor, and cyclin D1 and reduced immunoexpression of p21/waf1 and p27/kip1 {1828}. Diffuse TP53 nuclear immunoexpression has been found in 4 of 5 cases {1803,1828, 2421}.  

 Electron microscopy

 Ultrastructurally, tumour cells occasionally have a squamous or glandular differentiation not apparent on conventional light microscopic examination {1816, 2836}. Neuroendocrine differentiation is rare; neurosecretory granules have been described in 3 cases {1151,1432,1828}. Prominent desmosome-like junctions connect the tumour cells.

Genetics

 Genetic studies of salivary gland large cell carcinoma are scant. TP53 mutation has been detected in two of three cases, and 1 case demonstrated loss of heterozygosity (LOH) at chromosome 17p {1803,1828}. Two cases of large cell neuroendocrine carcinoma exhibited LOH at chromosome 9p21 {1828}.

Prognosis and predictive factors

 Large cell carcinoma is an aggressive tumour with a propensity for local recurrence, cervical lymph node metastases, and distant spread. However, one study has shown that cell size (small vs large type of carcinoma) has no influence on prognosis {1151}. Tumour size has been found to be a prognostic indicator; all patients with tumours larger than 4 cm died of disease with distant metastases {1151}.