Jhudit Pérez-Escuredo

Genetic and clinical aspects of wood dust related intestinal-type sinonasal adenocarcinoma: a review

Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare epithelial cancer of the nasal cavities and paranasal sinuses. Exposure to wood dust particles is a strong etiological factor making it a professional disease. These tumors are locally aggressive with frequent local recurrences in up to 50% of cases. Metastasis to regional lymph nodes and distant metastasis are less frequent (10%). Invasion of the duramater and local recurrence are frequent and the major cause of death. Standard therapeutic modalities include surgery followed by radiotherapy in advanced stages, sometimes with chemotherapy treatment. The molecular genetic mechanisms underlying the development and progression of this tumor is not understood. Histopathologically, ITAC resembles colorectal adenocarcinoma and have directed early genetic studies to search for similar genetic alterations. Recently, genome-wide studies have identified a recurrent pattern of chromosomal aberrations. This review aims to describe the clinico-pathological characteristics of this relatively unknown tumor and to summarize the knowledge on genetic and chromosomal analyses up to the present time.

Genome-wide analysis of genetic changes in intestinal-type sinonasal adenocarcinoma

Intestinal‐type sinonasal adenocarcinomas are rare tumors related to professional exposure to wood dust. Little is known about the genetic changes in these tumors.

KRAS and BRAF mutations in sinonasal cancer

OBJECTIVES [corrected] Despite improvements in the field of surgery and radiotherapy, the overall prognosis of sinonasal carcinomas is poor, mainly due to the difficulty to resect the tumour completely in this anatomically complex region. Therefore, there is great need for alternative treatments. Knowledge of the KRAS and BRAF mutational status would become clinically important with regard to the possible use of anti-EGFR therapies. MATERIAL AND METHODS DNA was extracted from paraffin embedded tumour samples from 57 cases of sinonasal squamous cell carcinoma (SNSCC) and from fresh frozen tumour samples from 58 cases of intestinal-type sinonasal adenocarcinoma (ITAC). Point mutations were analysed for KRAS exon 2 (codons 12 and 13) and BRAF (exon 15, V600E) by direct sequencing. RESULTS Neither KRAS nor BRAF showed any mutations in the SNSCC, whereas 7/58 (12%) ITAC harboured KRAS mutations and no BRAF mutations. All seven cases with KRAS mutation concerned well-differentiated and less aggressive (papillary and colonic type) ITAC, all patients being woodworkers and 4/7 tobacco smokers. CONCLUSION Neither of SNSCCs carried mutations in KRAS and BRAF and a low frequency of KRAS mutation was found in ITAC. This suggests that KRAS and BRAF mutations play a limited role in the development of sinonasal cancer and that mutation analysis is not useful as a screening test for sensitivity to anti-EGFR therapy in sinonasal cancer.

Wood dust–related mutational profile of TP53 in intestinal-type sinonasal adenocarcinoma

Intestinal-type sinonasal adenocarcinoma represents 8% to 25% of all malignant sinonasal cancer and is etiologically related to occupational exposure to wood dust. Despite its clear etiology, the mechanisms behind the carcinogenic effects of wood dust are unclear. Because it is known that carcinogens can leave specific mutational fingerprints, we aimed to analyze the spectrum of TP53 mutations and to relate the findings to the wood dust etiology of the patients. Forty-four primary tumors were examined for TP53 mutations by direct sequencing. In addition, p53 protein expression was analyzed by immunohistochemistry using a tissue microarray consisting of 92 tumors. We report a frequency of 41% (18/44) TP53 mutations and 72% (66/92) p53 immunopositivity in intestinal-type sinonasal adenocarcinoma, significantly related to wood dust, but not to tobacco etiology. G→A transition (50%, 9/18 cases) was the most common alteration detected, almost exclusively found in nonsmokers, whereas G→T (27%, 5/18 cases) was detected in smokers only. These data point to wood dust exposure as the causal factor in the mutagenesis of TP53, possibly caused by reactive nitrogen species generated through a chronic inflammatory process.

Microsatellite instability analysis of sinonasal carcinomas

OBJECTIVES: Intestinal-type sinonasal adenocarcinoma (ITAC) and squamous cell carcinoma of the nasal cavity (SCCNC) are histopathologically but not etiologically similar to colorectal adenocarcinoma or to laryngeal squamous cell carcinoma, respectively. Microsatellite instability (MSI) is involved in both tumors. The aim of this study was to investigate a possible role for MSI in the pathogenesis of two types of nasal carcinoma. MATERIAL AND METHODS: DNA obtained from frozen tumor samples of 41 ITACs and 24 SCCNCs was analyzed for shifts in five mononucleotide microsatellite loci by multiplex PCR. RESULTS: The allelic patterns of one ITAC (2%) and five SCCNCs (21%) revealed an allelic shift for at least one of the five loci, indicating microsatellite instability. CONCLUSION: MSI may be involved in squamous cell carcinoma, but not in adenocarcinoma of the nasal cavities.

Benign Lesions in Mucosa Adjacent to Intestinal-Type Sinonasal Adenocarcinoma

Occupational exposure to wood dust is a strong risk factor for the development of intestinal-type sinonasal adenocarcinoma (ITAC); however, knowledge on possible precursor lesions or biomarkers is limited. Fifty-one samples of tumor-adjacent mucosa and 19 control samples of mucosa from the unaffected fossa of ITAC patients were evaluated for histological changes and p53 protein expression. Mild dysplasia was observed in 14%, cuboidal metaplasia in 57%, intestinal metaplasia in 8%, squamous metaplasia in 24%, and cylindrocellular hyperplasia in 53% of cases. P53 immunopositivity was generally weak occurring most frequently in squamous metaplasia. Wood dust etiology did not appear of influence on the histological changes, but p53 showed a tendency for higher positivity. Dysplasia adjacent to tumor was indicative of subsequent development of recurrence. In conclusion, precursor lesions do occur in mucosa adjacent to ITAC. This is clinically important, because it may justify the screening of high-risk individuals such as woodworkers.

Adenocarcinomas nasosinusales tipo intestinal. Perfil inmunohistoquímico de 66 casos

INTRODUCTION AND OBJECTIVES Intestinal-type sinonasal adenocarcinomas are malignant epithelial tumours. Around 8-25% of all sinonasal malignant tumours are intestinal-type adenocarcinomas, which are related to wood dust exposure. Four histological subtypes have been described: papillary, colonic, solid and mucinous. We performed a pathological and immunohistochemical study in order to describe characteristics with prognostic, diagnostic and therapeutic value, and also to compare our results with previous studies. METHODS Sixty six tumour samples were analysed and protein expression of p53, p16, E-cadherin, β-catenin, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2/neu) and cyclooxygenase-2 (COX-2) was performed by tissue microarray blocks. RESULTS The 63% of cases were p53 positive; 37% showed nuclear staining with β-catenin and 100% with E-cadherin, while 98% showed membrane staining with β-catenin, 7% with EGFR, 8% with HER2/neu and 52% with COX-2; and 59% of the cases lost p16 expression. CONCLUSIONS Intracranial invasion was the worst prognostic associated event. Solid and mucinous tumours were the most aggressive histological subtypes. Intracranial invasion was more frequent in mucinous subtype tumours. Immunohistochemical results were similar in all tumour subtypes, except for mucinous tumours, which showed weak expression of E-cadherin and β-catenin. Comparing with previous studies, we found a lower expression of EGFR, HER2/neu and COX-2. The p16 expression was associated with worse survival and metastatic disease.

Localization of centromeric breaks in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) have very complex karyotypes that show all types of structural rearrangements. The most frequent aberrations are whole-arm translocations, which appear to have their breakpoints in centromeric or pericentromeric regions. We aimed to pinpoint the exact location of the breakpoints of these marker chromosomes with high-resolution cytogenetic and genetic analyses using microarray comparative genomic hybridization (CGH), multiplex ligation-dependent probe amplification (MLPA), and fiber fluorescence in situ hybridization (FISH). Among the seven cell lines in this study, six (84%) harbored one or more centromeric breakpoints or whole-arm translocations. In total, microarray CGH identified 163 breakpoints, 47 (29%) of which were in centromeric regions. Microarray CGH and MLPA results indicated that the translocation breakpoints were localized between the microarray oligonucleotide clones and MLPA probes closest to the centromere. High-resolution fiber-FISH revealed adjacent or minimally overlapping signals of probes that recognize the pericentromeric sequences of the two participating chromosomes. This indicates that whole chromosome arm translocation breakpoints occur within the pericentromeric chromatin and not the centromere core sequences.

Genomic profiling of intestinal-type sinonasal adenocarcinoma reveals subgroups of patients with distinct clinical outcomes

Patients with intestinal‐type sinonasal adenocarcinoma (ITAC) have an unfavorable prognosis and new therapeutic approaches are needed to improve clinical management.

Caracterización molecular de los carcinomas nasosinusales y sus implicaciones clínicas

Sinonasal carcinomas are rare tumours with an unfavourable prognosis whose management is difficult and complex, leading to high morbidity and mortality despite improvements in the field of surgery and radiotherapy. An elevated number of these tumours can be attributed to occupational exposure. In comparison with other head and neck malignancies, studies of molecular changes in these tumours are infrequent. This review was focused on findings about the epidemiology and molecular and phenotypic characterisation of sinonasal carcinomas, which can potentially be useful for diagnosis and treatment. The increasing knowledge about the molecular biology that underlies their carcinogenesis may help to identify precursor lesions, prognostic markers and markers that predict chemoradiotherapy response and, finally, to identify potential molecular targets that will expand treatment options.