Search

Aims: In the current study, we aimed to examine primary parotid squamous cell carcinoma (ParSCC) for the presence of high-risk human papillomavirus (HR-HPV) and associated molecular alterations., Methods and Results: Eight cases of ParSCC were retrieved after a detailed clinicopathological review to exclude the possibility of metastasis and/or extension from another primary site. HR-HPV status was determined on the basis of immunohistochemistry (IHC) for p16 expression and chromogenic in-situ hybridization (CISH) for HR-HPV. All cases were genotyped with a multiplexed mass spectrometry assay interrogating 91 hotspot mutations in eight cancer-related genes (EGFR, KRAS, NRAS, BRAF, PIK3CA, AKT1, MEK1 and ERBB2), and studied by fluorescence in-situ hybridization for PTEN copy number alteration. Three of eight cases (37.5%) were positive for the presence of HR-HPV by CISH and p16 IHC. One of three (33%) HR-HPV-positive cases harboured a PTEN hemizygous deletion, and one (33%) HR-HPV-positive case harboured a PIK3CA E545K somatic mutation. No alteration of the PTEN-PI3K pathway was detected in HR-HPV-negative tumours. Over a median follow-up period of 66.2 months, only the patient with the HR-HPV-positive PIK3CA-mutated tumour died of his disease, the remaining seven patients being disease-free., Conclusions: Given the established aetiological role of HR-HPV in other head and neck squamous cell carcinomas, it is likely that HR-HPV represents an oncogenic driver in the pathogenesis of more than one-third of ParSCCs. The presence of HR-HPV in ParSCC may be coupled with alterations in the PTEN-PI3K pathway. Further studies on HR-HPV and the molecular characterization of a larger number of ParSCCs are needed to determine the clinical significance of these findings., Competing Interests: Disclosure/conflict of interest: No competing financial interests exist for all contributory authors., (© 2016 John Wiley & Sons Ltd.)

Aims: Metastasizing pleomorphic adenoma (MPA) is a rare tumour, and its mechanism of metastasis still is unknown. To date, there has been no study on MPA genomics. We analysed primary and secondary MPAs with array comparative genomic hybridization to identify somatic copy number alterations and affected genes., Methods and Results: Tumour DNA samples from primary (parotid salivary gland) and secondary (scalp skin) MPAs were subjected to array comparative genomic hybridization investigation, and the data were analysed with NEXUS COPY NUMBER DISCOVERY. The primary MPA showed copy number losses affecting 3p22.2p14.3 and 19p13.3p123, and a complex pattern of four different deletions at chromosome 6. The 3p deletion encompassed several genes: CTNNB1, SETD2, BAP1, and PBRM1, among others. The secondary MPA showed a genomic profile similar to that of the primary MPA, with acquisition of additional copy number changes affecting 9p24.3p13.1 (loss), 19q11q13.43 (gain), and 22q11.1q13.33 (gain)., Conclusion: Our findings indicated a clonal origin of the secondary MPA, as both tumours shared a common profile of genomic copy number alterations. Furthermore, we were able to detect in the primary tumour a specific pattern of copy number alterations that could explain the metastasizing characteristic, whereas the secondary MPA showed a more unbalanced genome., (© 2015 John Wiley & Sons Ltd.)

Aims: In this study, we aimed to investigate the molecular mechanisms underlying the development of mucoepidermoid carcinoma (MEC)., Methods and Results: In 31 cases, we examined the MAML2 fusion status using reverse transcriptase-polymerase chain reaction, and HER2 and EGFR status using immunohistochemistry and chromogenic in-situ hybridization. MAML2 fusions were detected in 15 (57.7%) of 26 MECs analysed, including 11 of 16 (68.8%) low-grade, two of four (50%) intermediate-grade and two of six (33.3%) high-grade MECs. HER2 gene amplification and an increased EGFR gene copy number (with balanced chromosome 7 high-polysomy) were each detected in four of 28 (14.3%) MECs analysed. Irrespective of MAML2 fusion status, all seven high-grade MECs had an increased gene copy number of either HER2 or EGFR, in a mutually exclusive manner, whereas such abnormalities were extremely rare in low- and intermediate-grade MEC., Conclusions: These results suggest that HER2 or EGFR gene abnormality could play an important role in the development of high-grade MEC, and also in the progression from MAML2 fusion-positive low-/intermediate-grade to high-grade in a subset of MEC. Furthermore, we suggest that high-grade MEC comprises a heterogeneous group of tumours in terms of molecular pathogenesis, in particular MAML2 fusion status., (© 2013 John Wiley & Sons Ltd.)

Aims: To analyse the clinicopathological findings of extranasal CD56+ cytotoxic T- or NK-cell lymphomas in different organs and to compare Epstein-Barr virus (EBV)+ and EBV- lymphoma of non-blastoid cytomorphology., Methods and Results: Fifty-one cases of cCD3+ T-cell intracellular antigen (TIA-1)+ CD56+ lymphomas of extranodal/extranasal origin were included in the study. The primary sites of the CD56+ tumours were soft tissue (n = 10), the gastrointestinal (GI) tract (n = 13), the skin (n = 15), upper aerodigestive tract excluding nasal and nasopharyngeal regions (n = 11), the testis (n = 1), and parotid gland (n = 1). TCR gene rearrangement was detected in seven of 47 cases examined (16%). EBV was positive in 39 of 51 cases (76%). The positive rate of EBV was higher in tumours of soft tissue (80%), GI tract (92%), and skin (80%), and lowest in the upper aerodigestive tract excluding the nasal and nasopharyngeal region (50%). Tumours of the soft tissue and the upper aerodigestive tract tended to present with localized disease (P = 0.002). The 2-year survival rate was lowest for tumours of the GI tract (P = 0.0256). EBV- TCR- lymphoma showed less necrosis (P = 0.0133) and a better 2-year survival rate (P = 0.0066) than EBV+ TCR- lymphoma. Patients with EBV+ TCR+ lymphomas tended to present with localized disease, more often than EBV+ TCR- lymphoma (P = 0.0186). Significant prognostic factors in all CD56+ lymphomas were the site (P = 0.0256), EBV status (P = 0.0026), necrosis with or without perforation (P = 0.0338) and the presence of pleomorphic large tumour cells (P = 0.0428). Cox's regression analysis adjusting for other pathological parameters showed EBV status to be the only independent prognostic factor (P = 0.018)., Conclusions: Extranodal CD56+ EBV- lymphoma at extranasal sites is a clinically less aggressive malignancy and displays less necrosis than CD56+ EBV+ lymphoma. Because CD56+ EBV+ TCR+ lymphomas show similar pathological and clinical findings to CD56+ EBV+ TCR- lymphomas, nasal-type NK/T-cell lymphomas at extranasal sites should be diagnosed as such on the basis of EBV+, cytotoxic T or NK phenotype irrespective of the genotype determined by molecular study.

Aims: Salivary duct carcinoma is a highly malignant salivary gland tumour with aggressive clinical behaviour, characterized by histological resemblance to invasive ductal carcinoma of the breast. Amplification of HER-2/neu oncogene and over-expression of its gene product have both prognostic and therapeutic implications in breast cancer. Recent report on salivary duct carcinomas for HER-2/neu using immunohistochemistry (IHC) has shown over-expression in most cases. However, correlation between IHC and molecular genetic analysis of HER-2/neu in salivary duct carcinoma has not yet been performed., Methods and Results: We have now evaluated 11 cases of salivary duct carcinomas for HER-2/neu status using IHC and fluorescent in-situ hybridization (FISH). To our knowledge, this is the first molecular genetic analysis of HER-2/neu in salivary duct carcinoma., Conclusions: In immunohistochemistry, over-expression of HER-2/neu protein was identified as distinct membrane staining in most carcinoma cells in all our salivary duct carcinoma cases, while only four cases revealed an amplification of HER-2/neu gene by means of FISH analysis. Both amplified and non-amplified salivary duct carcinomas with strong immunohistochemical staining for HER-2/neu protein were associated with poor clinical outcome for the patients. Apparently, HER-2/neu protein over-expression could also be controlled by mechanisms other than gene amplification. In the group of salivary gland tumours other than salivary duct carcinoma, strong over-expression was detected only in three cases of carcinoma ex pleomorphic adenoma. Thus, over-expression of HER-2/neu protein is also a useful marker of malignant transformation in pleomorphic adenomas.

Aims: Pleomorphic adenomas of the salivary glands are characterized by their high tissue diversity. Many studies have explored the derivation and differentiation of the neoplastic cells. We investigated the composition of the collagenous extracellular tumour matrix and could show a specific biochemical composition pattern in the different tumour areas., Methods and Results: In epithelially differentiated acinar and ductal areas there was positive staining for basement membrane collagen type IV and no, or only scarce, staining for collagen types I, II, III, or VI. Solid areas mostly lacked any extracellular matrix. In areas with fibrous tissue-like appearance, the fibroblast-typical interstitial collagen types I, III and VI were seen. Chondroid areas showed abundantly the characteristic cartilage components, collagen type II and, pericellularly, type VI collagen., Conclusions: Our data show the presence of fibroblastic and chondrocytic cell differentiation in pleomorphic adenomas. Thus, they confirm that these neoplasms display, besides epithelial cell types, also real mesenchymal cell and tissue types. Differences in the abundance and the biochemical composition of the extracellular tumour matrix account largely for the morphological heterogeneity of pleomorphic adenomas of the salivary glands.

Aims: Primitive neuroectodermal tumour (PNET) is a malignant small round cell tumour that exhibits neuroepithelial differentiation. Isolated cases of PNET have been reported in visceral sites such as the kidney, uterus, ovary, testis, urinary bladder and pancreas. We present two cases of PNET of the parotid gland., Methods and Results: The first case was a 60-year-old woman, who presented with a parotid swelling of 10 months duration. The second case was a 45-year-old man, who presented with a recurrent temporofacial swelling of 6 months duration. Histological evaluation, in conjunction with immunohistochemistry, confirmed the diagnosis of PNET., Conclusions: This is the first documentation of PNET of the salivary gland. The probable origin is from the facial nerve.