Salivary duct carcinoma

 Definition

 An aggressive adenocarcinoma which resembles high-grade breast ductal carcinoma.

ICD-O code 8500/3

 Synonyms

 Cribriform salivary carcinoma of excretory ducts, high-grade salivary duct carcinoma

Epidemiology

 Salivary duct carcinoma (SDC) is an uncommon, but not a rare form of salivary malignancy. De novo and/or expleomorphic adenoma, SDC represents 9% of salivary malignancies. The male:female ratio is at least 4:1. Most patients present after age 50 {135,259, 1488}. The parotid is most commonly involved, but submandibular, sublingual, minor salivary gland, maxillary and laryngeal tumours have been reported {682, 745,1383,2021,2583,2862,2909}.

 Etiology

A unique case of SDC arising in a longstanding chronic obstructive sialadenitis has been reported {1113}.

Clinical features

 Patients with SDC typically present with recent onset of a rapidly growing tumour that may fluctuate in size. Occasional patients have longer clinical histories. Pain and facial paresis may be present.

 Macroscopy

SDC are usually firm, solid, tan, white or grey, with a cystic component. Infiltration of the adjacent parenchyma is usually obvious, but occasional tumours may appear to be circumscribed. SDC may also arise as the malignant component of a carcinoma ex pleomorphic adenoma, so that the macroscopic features of pleomorphic adenoma may also be present.

Tumour spread and staging

 For SDC, perineural spread (60%) and intravascular tumour emboli (31%) are common. Most patients present with Stage III or IV disease, as lymph nodes are positive in 59% of patients {135}.

Histopathology

 SDC resembles intraductal and infiltrating mammary duct carcinoma, both architecturally and cytologically. The diagnostic “ductal lesion” comprises pleomorphic, epithelioid tumour cells with a cribriform growth pattern, “Roman bridge” formation, and intraductal comedonecrosis. The tumour infiltrates and metastasizes with a cribriform pattern, or it totally recapitulates the intra sialodochal “ductal lesion”. Solid and papillary areas may be seen, with psammoma bodies, as well as evidence of squamous differentiation. Cytologically, these cells have abundant, pink cytoplasm and large pleomorphic nuclei with prominent nucleoli and coarse chromatin. The cytoplasm may also be densely eosinophilic, granular, or oncocytic. Mitotic figures are usually abundant. Goblet cells are not seen. Rare tumours may have a prominent spindle cell or sarcomatoid growth pattern similar to the metaplastic ductal carcinomas of the breast {1064,1819,}. The mucin-rich SDC is a recently described variant of SDC {2371}. The tumour is composed of areas of typical SDC, but in addition, contains mucin lakes with islands of carcinoma cells. Another variant showing an invasive micropapillary component has also been reported {1820}.

Immunoprofile

 SDC is immunoreactive for low- and high-molecular- weight cytokeratin, and markers such as carcinoembryonic antigen (CEA), LeuM1, and epithelial membrane antigen (EMA) {579,1488}. Strong nuclear reactivity for androgen receptors (AR) is reported in all SDC {1265,1488, 2371}. SDC cells are focally positive for apocrine marker GCDFP-15 and mitochondrial antigen (MIA), and typically negative for S-100 protein, myoepithelial markers, estrogen and progesterone receptors. Variable expression of prostatic markers (prostate specific antigen, prostatic acid phosphatase) is seen {555}. The MIB1 proliferative index is high, with an average value of 43% (range 25-80%). Most SDC show positive distinct membrane staining for HER- 2/neu protein {1644,2392,2393}.

Differential diagnosis

Other diagnoses to consider for SDC include metastatic breast and squamous carcinomas, oncocytic carcinoma and mucoepidermoid carcinoma. Despite a superficial resemblance to squamous carcinoma, this diagnosis can be discarded as soon as the infiltrating cribriform pattern is recognized. Identification of sialodochodysplasia supports a primary parotid origin. Goblet cells are not seen with SDC (aside from intraductal goblet cell metaplasia), thus ruling out mucoepidermoid carcinoma.

Genetics

Only two studies of these tumours have been published. Seven of eight tumours had LOH in at least one marker on chromosome 9p21 {351} in one study. In the other study, a high incidence of LOH was found at 6q,16q, 17p and 17q regions {1110}. Amplification of HER-2/neu gene and gene product overexpression are reported in SDC {725,1644,1803,2392,2393}. Mutations and overexpression of the TP53 gene and protein are frequent {1110,1803,1823}. Loss of heterozygosity at microsatellite loci, TP53 point mutations and frequent alterations of certain loci on chromosome arm 6q have been reported {1110}. The chromosomal locus 9q21 contains the CDKN2A/p16 tumour suppressor gene that has been implicated in a variety of tumour types, including SDC {351}. More polymorphic genetic markers located at this particular region suggest that inactivation of CDKN2A/p16 gene is associated with progression of SDC {351}.

 Prognosis and predictive factors

SDC is one of the most aggressive salivary malignancies. A review of 104 cases concluded that 33% of patients developed local recurrence and 46% developed distant metastasis {135}. Sites for distant metastasis include lungs, bones, liver, brain and skin. Sixty-five percent of patients died of disease, between 5 months to 10 years, usually within 4 years of diagnosis. The clinical course is characterized by early distant metastases. Tumour size, distant metastasis, and HER-2/neu overexpression are putative prognostic parameters for SDC, while expression of p53 protein, DNA aneuploidy, and proliferative activity do not correlate with outcome {2393}. The clinical outcome for the mucin-rich variant of SDC is similar to that of conventional SDC {2371}. The invasive micropapillary variant appears to be particularly aggressive {1820}.