Intestinal-type Sinonasal Adenocarcinoma Research Articles

Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma.

Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.

Gene Methylation Profiling in Sinonasal Adenocarcinoma and Squamous Cell Carcinoma.

To identify epigenetic events in intestinal-type sinonasal adenocarcinoma (ITAC) and sinonasal squamous cell carcinoma (SNSCC) and to evaluate their relation to clinicopathologic features and follow-up data. Retrospective study. Academic research hospital. The methylation status of 23 genes in 50 ITACs and 32 SNSCCs was analyzed by methylation-specific multiplex ligation-dependent probe amplification and its relation to clinicopathologic features and follow-up data. Gene methylation was observed in 50% of all tumors. Recurrent methylated genes in SNSCC were RASSF1 and CDH13 (for both, 6 of 32 cases), CHFR (4 of 32 cases), and TIMP3 (2 of 32 cases). None of these genes showed significant correlation to clinicopathologic features or overall survival. In ITAC, recurrent methylated genes were CDH13 (18 of 50 cases), ESR1 (13 of 50 cases), APC (7 of 50 cases), TIMP3 (5 of 50 cases), CASP8 (3 of 50 cases), and HIC1 and RASSF1 (for both, 2 of 50 cases). Papillary and colonic ITAC subtypes carried a mean of 1.26 gene methylations per tumor versus 0.63 in solid and mucinous subtypes. Methylation of TIMP3 was associated with a significantly worse survival in ITAC patients. ITAC carries a higher number and a different profile of gene methylations as compared with SNSCC. Gene methylation plays a greater role in papillary and colonic ITAC subtypes, which may indicate a different tumorigenic pathway for these ITAC subtypes. These findings could be used as prognosticators and may have implications for future individualized therapies based on epigenetic changes.

Intestinal‐type sinonasal adenocarcinomas: The road to molecular diagnosis and personalized treatment

Sinonasal intestinal-type adenocarcinomas (ITACs) are epithelial tumors of the nasal cavity and the paranasal sinuses, often related to professional exposure to organic dust, mainly wood or leather. It is a rare cancer. If resectable, surgery is the treatment of choice. Postoperative radiotherapy is often indicated to increase local control. Systemic treatment (chemotherapy, targeted agents, or immunotherapy) of irresectable ITACs and/or metastasized disease is less standardized. Articles on ITAC histopathology, molecular profile, and current treatment options of this specific tumor were identified and reviewed, using the electronic databases Pubmed, Medline, Cochrane, and Web of Science. This article reviews what is currently known on the histopathology, tumorigenesis, molecular characteristics, and standardized treatment options of ITAC. More translational research is needed to identify druggable targets that may lead to a personalized treatment plan in order to improve long-term outcome in patients with locally advanced and/or metastasized ITAC. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1570, 2016.

P19 Evidence for histological lesions precursor to intestinal-type sinonasal adenocarcinoma

Background Intestinal-type sinonasal adenocarcinomas (ITAC) are rare tumors, related to occupational exposure to wood and leather dust. Clinical symptoms are often indistinguishable from symptoms of patients with benign sinonasal disease, and as a consequence, patients frequently present with advanced-stage tumors. Multistep carcinogenesis through various histological changes accompanied by accumulating genetic alterations has not been demonstrated for ITAC. The aim of this study was to identify histological changes precursor to ITAC that may be useful for early detection for tumors in individuals at risk. Material and methods H&E stained paraffin sections from mucosa adjacent to primary tumor or recurrence of 136 patients with ITAC were evaluated for the presence of respiratory or olfactory epithelium, dysplasia, cuboid metaplasia, squamous metaplasia, and cylindrocellular hyperplasia. Protein expression of differentiation markers CK7, CK20, CDX2, B-III tubulin, Lysozyme, MUC2 and MUC5, and cancer-related genes B-catenin, p53, p16 and Cox2 were analyzed by immunohistochemistry. Results Our preliminary data revealed cuboid metaplasia in more than half of the cases, while intestinal metaplasia and dysplasia, accompanied by a switch to CK7−/CK20+/CDX2+ and in some cases p53/Cox2 expression, occurred in approximately 10–15%. Discussion Possible lesions precursor to ITAC were found infrequently however it may be speculated that these lesions often become destroyed by the growth of the ITAC tumor mass. Therefore we suggest that histological evaluation aided by CK20 and perhaps other biomarkers may be used for screening individuals at risk.

P35 Genomic profiling of intestinal-type sinonasal adenocarcinoma reveals a subgroup of patients with favourable clinical outcome

Intestinal-type sinonasal adenocarcinomas (ITAC) are rare tumors, related to occupational exposure to wood and leather dust. Patients with ITAC carry a poor prognosis and recurrent disease is the main cause of mortality. The purpose of this study was to analyse genome-wide copy number alterations (CNAs) in a large series of cases, aiming to identify genetic events involved in ITAC development and progression. DNA was isolated from 61 frozen ITAC tissue samples including all histological subtypes and analysed by high-resolution microarray CGH. Results were correlated to previously obtained genetic and immunohistochemical data and to clinico-pathological characteristics and follow-up data. All but three cases showed CNAs. Most frequent gains were found at chromosomal loci 5p, 7p, 8q, 12p and 20, whereas recurrent deletions were observed at 4q, 5q, 8p, 10q, 17p and 18q. High level amplifications included 7p12, 8q24, 11q13 and 19q11. Cluster analysis revealed a subgroup of cases characterized by carrying few CNAs (mean 8 versus 45). In addition, these cases showed absence of TP53 mutation and more frequent overexpression of COX2 and NFkB compared to the other cases. Overall survival was significantly better in this subgroup (p = 0.012). Genomic profiling revealed a subset of patients with ITAC with favourable clinical outcome, independent from established prognostic clinico-pathological parameters such as tumor stage and histological subtype. It may be speculated that this subset of tumors arises through a process of tumorigenesis that does not involved gross chromosomal instability as in the majority of epithelial tumors.

P18 Clinical management of intestinal-type sinonasal adenocarcinoma: A monoinstitutional experience of 165 cases

Introduction Intestinal-type sinonasal adenocarcinomas (ITAC) are rare tumors, related to occupational exposure to wood and leather dust. Patients with ITAC carry a poor prognosis and recurrent disease is the main cause of mortality. The low incidence of ITAC has hampered diagnosis, genetic analyses, classification, and staging, and prevented the accumulation of clinical experience at individual institutions. The aim of this study was to describe the clinical, pathological and follow-up data of a large series of cases treated in one single institute. Material and methods A total of 165 patients diagnosed with ITAC and treated in our hospital between 1978 and 2014 were included and the following variables were studied: gender, age, etiological factors, histopathological features, localization, surgical approaches, complementary treatment, clinical evolution and survival. Results The great majority of patients was male (164/165), the median age was 65 years (28–92 years), and 87% had a history of wood dust exposure. All tumors were localized in the ethmoid sinus, the most frequent histological subtype being colonic, followed by mucinous, papilar and solid type. At the time of presentation, 13% showed intracranial, 19% dura mater and 13% periorbital involvement, in total 34% of cases were stage III and 32% stage IV. The main treatment was the surgery, with different surgical approaches including craneofacial resection, craneofacial endoscopic resection and maxillectomy. Complementary radiotherapy was given in 95% of the patients. On average, patients remained 18 months disease-free and the overall 5-year survival was 45%. Conclusion Advances in surgical and radiotherapeutic approaches have improved management of ITAC although limited progress has been made in chemotherapy, partly owing to the difficulty of recruiting a sufficient number of patients for clinical trials. The study of molecular tumorigenic pathways and the testing of alternative treatment strategies would greatly benefit from wider multi-institutional collaboration, and we strongly support such collaborative efforts.

A Subset of Sinonasal Non-Intestinal Type Adenocarcinomas are Truly Seromucinous Adenocarcinomas: A Morphologic and Immunophenotypic Assessment and Description of a Novel Pitfall.

While sinonasal intestinal type adenocarcinoma (ITAC) is defined by an intestinal phenotype, non-intestinal type adenocarcinoma (non-ITAC) is traditionally viewed as a diagnosis of exclusion, despite previous implication of a seromucinous phenotype and similarity to sinonasal seromucinous hamartomas (SSH). We performed a comparison of clinicopathologic and immunophenotypic features of ITAC, non-ITAC and SSH using traditional discriminatory markers and new markers of seromucinous differentiation. Twenty-three non-ITAC, 17 ITAC, and 5 SSH were retrieved (1987-2014). As expected, ITAC occurred predominantly in the nasal cavity in elderly patients (mean age 65years) with a striking male predilection (15:2). Regardless of grade/subtype, all ITAC were invariably CK20 and CDX2 positive, and many (11/15) showed some CK7 positivity. Non-ITAC occurred in younger individuals (mean age 51years) with a slight female predilection (male to female ratio: 10:13) and showed diverse morphologic patterns and grades, some with morphologic similarity to SSH. SSH occurred in younger individuals (mean age 33years). Non-ITAC and SSH were invariably CK7 positive and CK20 negative, however, 4/22 non-ITAC and 2/5 SSH showed squamoid morular metaplasia that aberrantly expressed CDX2 and co-expressed nuclear β-catenin. Markers of seromucinous differentiation (S100, DOG1, and SOX10) were essentially absent in ITAC, but present to varying degrees in the majority of non-ITAC and all SSH. Thus, the term 'seromucinous adenocarcinoma' is the more appropriate designation for non-ITAC. Squamoid morules in non-ITAC and SSH may be an immunophenotypic pitfall given the aberrant CDX2 expression.

Intestinal-Type Sinonasal Adenocarcinoma: A Rare Entity with Review of Literature

Intestinal-type sinonasal adenocarcinoma accounts for about 3% of cancers of the upper aero-digestive tract. It is commonly seen in men in the age group of 55-60 years. We present the case of a 60-year-old woman having extensive disease in the right half of the nasal cavity extending to the dura of the anterior cranial fossa, and the right orbital contents. The patient was given induction chemotherapy to make the condition surgically amenable, but the regression was modest, and hence she has been put on concurrent chemo-radiotherapy.

Intestinal metaplasia of the sinonasal mucosa adjacent to intestinal-type adenocarcinoma. A morphologic, immunohistochemical, and molecular study.

It has been hypothesized that the development of sinonasal intestinal-type adenocarcinoma (ITAC) occurs through intestinal metaplasia (IM) of the respiratory and/or glandular epithelium. The aim of this study was to characterize the histological, immunohistochemical, and molecular features of sinonasal IM. Histologic slides from 29 consecutive surgical specimens of ITAC were retrieved. Sections were stained for CDX2, cytokeratin 20 (CK20), MUC2, and p53. The status of TP53 gene exons 4-9 was assessed separately in areas of IM and in ITAC. Foci of IM were detected in eight cases (27.5%). They were all positive for CK20 and CDX2, while MUC2 was detected in six cases (75%). In six cases (75%), the metaplastic foci showed signs of dysplasia, including nuclear enlargement with increased nucleus to cytoplasm ratio, nuclear hyperchromasia, loss of nuclear polarity, and presence of prominent nucleoli. P53 nuclear immunoreactivity was observed in four cases. TP53 gene sequencing was successfully performed in six cases and revealed the same mutation in both IM and ITAC in two cases (c.832C > T and c.215G > C), while another ITAC showed a mutation that was not present in the adjacent IM (c.536A > G). In conclusion, our study suggests a possible clonal relationship between areas of sinonasal IM and ITAC, indicating that IM may represent a precursor lesion of ITAC. Improving the knowledge on the morphological and molecular features of IM is a key step to identify reliable biomarkers to determine the risk of sinonasal ITAC development.

Primary Intestinal-type Adenocarcinoma of the Nasal Cavity: A Case Report.

We report a rare case of sinonasal intestinal-type adenocarcinoma in the nasal cavity. A 31-year old man represented with headache and epistaxis. We identified a malignant tumour, which is a rare pathology, with detailed physical examination, anterior rhinoscopy, computed tomography scan, magnetic resonance imaging and histopathologic examination. Endoscopic excision of the tumour was performed. After three years of follow-up of the patient in our clinic, there was no sign of any recurrence.

Study of MET protein levels and MET gene copy number in 72 sinonasal intestinal-type adenocarcinomas.

Sinonasal intestinal-type adenocarcinomas (ITACs) have a poor prognosis, and are defined on the basis of their morphological similarities to colorectal adenocarcinomas. MET signaling pathway is involved in oncogenesis in various cancers. Nothing is currently known about the role of MET in ITACs. In a series of 72 ITACs, we investigated MET protein levels by immunohistochemistry (IHC) and gene copy number by in situ hybridization. These findings were analyzed as a function of clinical data, histological typing, and patient outcome. MET protein was overproduced in 64% of cases and chromosome 7 polysomy was observed in 52% of cases. No tumor displayed MET amplification. The presence of mucinous or solid histological components, T3/T4 tumors, and incomplete resection were associated with a poor outcome. MET is overproduced in about two third of ITACs, suggesting a role for the MET signaling pathway in the oncogenesis of these tumors.

Endoscopic resection followed by adjuvant radiotherapy for sinonasal intestinal-type adenocarcinoma: Retrospective analysis of 30 consecutive patients

Intestinal-type adenocarcinoma (ITAC) is a rare and locally aggressive occupation-related tumor. Currently, endoscopic-assisted resection and advances in irradiation modalities (3D conformal radiotherapy/intensity-modulated radiation therapy [IMRT]) are emerging as an alternative to traditional open surgery and conventional radiotherapy. Retrospective analysis of 30 consecutive patients affected with sinonasal ITAC, primarily treated by an endoscopic approach followed by 3D conformal radiotherapy/IMRT at a single institution, from 2003 to 2010. The 5-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and recurrence-free survival (RFS) were 72.7% ± 9.6%, 78% ± 9.5%, 67.9% ± 10.7%, and 69.2% ± 9.4%, respectively (mean follow-up, 48 months). No major complications or serious toxicities were observed. Prognostic factors were stage of disease at diagnosis, development of recurrences, status of surgical margins, grading, tumoral pattern of growth, and proliferative index (Ki-67). The low morbidity of endoscopic approaches, the acceptable toxicity of modern irradiation modalities, and these promising survival rates, indicate that this treatment strategy might be considered a safe, minimally invasive, and maximally effective option for treating selected sinonasal ITAC.

Genetic Similarities between Ethmoidal Adenocarcinoma and Colorectal Adenocarcinoma: Towards a New Targeted Therapy?

Background: To compare the genetic profile and phenotype of sinonasal Intestinal Type AdenoCarcinoma (ITAC) and colorectal adenocarcinoma. Methods: Between 1983 and 2001, 41 patients were treated for ethmoidal adenocarcinoma at Rouen University Hospital. All pathologic specimens were reassigned according to the new 2005 World Health Organization classification. Immunohistochemical study was carried out to evaluate EGFR and CDX2 expression. Thirty-eight out of the 41 tumor specimens had sufficient DNA for KRAS and EGFR mutation analysis. SNaPshot® multiplex system was used to determine presence of the most common mutations (located in exons 18, 19, 20 and 21 for EGFR and in exon 2 [codon 12 and 13] for KRAS). Results: Of the 41 patients, there were 37 men and four women. Mean age at presentation was 63.6 years (range: 40.7-86.4 years). Occupational exposure was documented for 32 patients, with 31 cases of wood exposure and one of leather exposure. Of the 38 tumors genotyped, 35 were ITAC (33 men and two women) and wood exposure was found in 29 (85%) of these patients. CDX2 expression was present in 31 out of the 35 ITAC (89%) and absent in the 3 non-intestinal adenocarcinomas. EGFR was expressed in 29 out of the 35 ITAC (83%) with different expression: 19 (56 %) 1+, 7 (21%) 2+ and 3 (6%) 3+ immunopositivity and the 3 non ITAC disclosed 1+ EGFR positivity. No EGFR mutation was found in the series. For KRAS, 5 out of the 35 ITAC (14%) disclosed KRAS exon 2 mutation and the 3 non-intestinal adenocarcinomas were KRAS wild type. Conclusion: CDX2 immunohistochemistry could be a useful tool for discriminating ITAC. Phenotype and genotype similarities between ITAC and colorectal carcinomas could lead to clinical trials using anti-EGFR therapy in patients with locally advanced or metastatic ITAC.

Sinonasal Carcinoma – A Report of Two Cases

Sinonasal carcinomas are rare and account for 3% of all malignant tumours of head and neck. Squamous cell carcinoma is the commonest histological variant. We present a case of sinonasal squamous cell carcinoma in a 52-years-male and another rare case of intestinal type sinonasal adenocarcinoma in 50-years-male.

Low Prevalence of K-RAS, EGF-R and BRAF Mutations in Sinonasal Adenocarcinomas. Implications for Anti-EGFR Treatments

We have previously shown that a subset of sinonasal intestinal-type adenocarcinomas (ITAC) shows activation of the epidermal growth factor-receptor (EGFR) pathway. In this study we examine the status of the EGFR, KRAS and BRAF genes in a series of sinonasal intestinal (ITAC) and non-intestinal type adenocarcinomas (non-ITAC). Eighteen ITACs and 12 non-ITACs were studied immunohistochemically for EGFR expression. Point mutations were analyzed for EGFR exons 19 and 21, KRAS exon 2 and BRAF exon 15 by direct sequencing. Non-ITACs showed significantly higher expression of EGFR (p = 0.015). Mutation analysis revealed one ITAC with EGFR and one ITAC with KRAS mutation, while two non-ITACs presented mutation of BRAF. We conclude that a subset of sinonasal adenocarcinomas shows overexpression of EGFR, while activating mutations of the signaling cascade downstream of EGFR are rare, suggesting that these tumors could be good candidates for anti-EGFR therapies.

Among Sinonasal Tumors, CDX-2 Immunoexpression is not Restricted to Intestinal-Type Adenocarcinomas

Intestinal-type adenocarcinoma (ITAC) is a rare form of sinonasal cancer characterized by an association with exposure to industrial dusts, aggressive clinical behavior, and histologic/immunophenotypic similarity to tumors of the gastrointestinal tract. ITAC is sometimes very poorly differentiated and difficult to distinguish from other sinonasal neoplasms, particularly in a limited biopsy. CDX-2 and cytokeratin 20 are consistently immunoreactive in ITAC and as a result, these immunostains are often used to support the diagnosis. However, CDX-2 and cytokeratin 20 have not been tested on a broad range of sinonasal tumors, so their specificities remain unknown. Immunohistochemistry for CDX-2 and cytokeratin 20 was performed on 6 sinonasal ITACs as well as 176 non-intestinal-type sinonasal neoplasms. CDX-2 and cytokeratin 20 were positive in all 6 cases of ITAC. CDX-2 immunoexpression was also observed in 17 of 176 (10 %) non-intestinal-type tumors including 6 of 16 (38 %) sinonasal undifferentiated carcinomas, 8 of 81 (10 %) squamous cell carcinomas (including 5 of 39 non-keratinizing variants), 2 of 20 (10 %) salivary-type adenocarcinomas, and 1 of 2 (50 %) small cell carcinomas. In contrast, among non-intestinal types of sinonasal tumors, cytokeratin 20 was only focally observed in 1 of 176 non-intestinal tumors (a non-keratinizing squamous cell carcinoma). All cases of non-intestinal surface-derived adenocarcinoma and esthesioneuroblastoma were negative for both markers. Both CDX-2 and cytokeratin 20 are highly sensitive for the diagnosis of sinonasal ITAC, but cytokeratin 20 is more specific. CDX-2 staining may be observed in other high grade tumor types, especially sinonasal undifferentiated carcinoma and non-keratinizing squamous cell carcinoma. As a result, in the setting of a poorly differentiated sinonasal carcinoma the diagnosis of ITAC should not be based on CDX-2 immunoexpression alone. Clear-cut glandular differentiation and cytokeratin 20 immunoexpression are more reliable features.

Epidermal growth factor receptor expression and KRAS and BRAF mutations: study of 39 sinonasal intestinal-type adenocarcinomas

Sinonasal intestinal-type adenocarcinomas (ITACs) are uncommon tumors of poor prognosis defined by their similarities to colorectal adenocarcinomas. The involvement of the epidermal growth factor receptor (EGFR) pathway in colorectal adenocarcinoma oncogenesis is well established, and the same is expected to apply to ITACs. In a series of 39 ITACs, we investigated EGFR amplification and chromosome 7 polysomy by fluorescence in situ hybridization; EGFR, KRAS, and BRAF mutational status by polymerase chain reaction sequencing; EGFR variant messenger RNA expression by quantitative reverse transcriptase polymerase chain reaction; and EGFR protein expression by immunohistochemistry with antibodies targeting the extracellular domain, the intracellular domain, and the phosphorylated isoform. The findings were analyzed with respect to clinical data, histologic typing, and patient outcome. EGFR amplification was observed in 3 cases with a focal distribution. EGFR proteins were overexpressed in all these foci with both extracellular domain and intracellular domain antibodies, suggesting involvement of the whole receptor. Chromosome 7 polysomy was observed in 15 cases and was not associated with EGFR protein expression. EGFR, KRAS, or BRAF mutations were observed in 5 different cases. The EGFRvIII mutant was not detected. In all cases, EGFR variants were expressed. There was no association between these molecular features and patient survival. In conclusion, (1) our study revealed various EGFR expression patterns in ITACs, indicating tumor heterogeneity; (2) EGFR amplification should be distinguished from chromosome 7 polysomy; (3) fluorescence in situ hybridization analysis could be guided by immunohistochemistry; and (4) ITACs share common alterations of the EGFR pathway with colorectal adenocarcinomas, except for a lower frequency of KRAS and BRAF mutations.

Trail Overexpression Inversely Correlates with Histological Differentiation in Intestinal-Type Sinonasal Adenocarcinoma

Introduction. Despite their histological resemblance to colorectal adenocarcinoma, there is some information about the molecular events involved in the pathogenesis of intestinal-type sinonasal adenocarcinomas (ITACs). To evaluate the possible role of TNF-related apoptosis-inducing ligand (TRAIL) gene defects in ITAC, by investigating the immunohistochemical expression of TRAIL gene product in a group of ethmoidal ITACs associated with occupational exposure. Material and Methods. Retrospective study on 23 patients with pathological diagnosis of primary ethmoidal ITAC. Representative formalin-fixed, paraffin-embedded block from each case was selected for immunohistochemical studies using the antibody against TRAIL. Clinicopathological data were also correlated with the staining results. Results. The immunohistochemical examination demonstrated that poorly differentiated cases showed a higher percentage of TRAIL expressing cells compared to well-differentiated cases. No correlation was found with other clinicopathological parameters, including T, stage and relapses. Conclusion. The relationship between upregulation of TRAIL and poorly differentiated ethmoidal adenocarcinomas suggests that the mutation of this gene, in combination with additional genetic events, could play a role in the pathogenesis of ITAC.

A Case of Papillary Intestinal Type Sinonasal Adenocarcinoma of the Nasal Cavity

Malignant tumors of the sinonasal tract are relatively rare and adenocarcinomas of various types account for 10% to 20% of primary malignancies of the nasal cavity and paranasal sinuses. According to the classification of World Health Organization, primary adenocarcinomas of the si nonasal tract can be initially classified as salivary and non-salivary types, and non-salivary types are further divided into intestinal and non-intestinal types. The authors experienced a case of papillary intestinal type sinonasal adenocarcinoma of the right nasal cavity in a 59-year-old woman, which was resected successfully via endoscopic approach. We present the clinical characteristics, pathology, treatment, and prognosis of the tumor with a review of the literature. � Korean J Otorhinolaryngol-Head Neck Surg 2013;56:310-3 Key WordsZZNasal cavity ㆍPapillary adenocarcinoma ㆍSinonasal.

EGFR status and KRAS/BRAF mutations in intestinal-type sinonasal adenocarcinomas

Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour that is etiologically related to professional exposure to wood dust and exhibits a poor prognosis. Treatment alternatives to surgery and radiotherapy are needed and may be found in anti-EGFR agents. EGFR gene copy number gains and KRAS/BRAF mutations have been reported to act as positive and negative predictors, respectively, of therapeutic response to EGFR targeted therapies in colorectal adenocarcinoma, a tumour type claimed to be genetically similar to ITAC. Therefore, the aim of this study was to evaluate the occurrence and consequence of EGFR alterations and KRAS and BRAF mutations in a large series of ITAC. EGFR protein expression was studied in 98 paraffin embedded tissue samples, organized in a tissue microarray. Gene copy number analysis was performed by FISH using the same tissue microarray, complemented by microarray CGH and MLPA analysis on DNA extracted from 65 fresh frozen tissues. Mutations in EGFR, KRAS and BRAF were analysed by direct sequencing on 65 fresh frozen tissues. EGFR gene copy number gains were observed in 45%, and protein over-expression in 21% of the cases. No mutations were found in EGFR or BRAF, while KRAS mutations were present in 12% of the cases. Neither protein overexpression nor gene copy number gain correlated to histological subtype, tumour stage or clinical follow-up. In the largest series of ITAC published to date, and using a number of different techniques, EGFR alterations were frequently observed. Although apparently not useful as a prognostic factor, there may be a basis for investigating EGFR targeted therapies in this group of patients, especially because negative response predictors such as KRAS and BRAF mutations are infrequent or absent, respectively.