Simon Andreasen

Pleomorphic adenoma of the parotid gland 1985-2010: A Danish nationwide study of incidence, recurrence rate, and malignant transformation.

Pleomorphic adenoma is the most frequent salivary gland tumor and is known for its tendency to recur and for its ability to transform to carcinoma ex pleomorphic adenoma (Ca‐ex‐PA). Along with pleomorphic adenoma demographics, we present the first nationwide study with long‐term follow‐up on these topics.

HPV-related Multiphenotypic Sinonasal Carcinoma

Human papillomavirus (HPV)–related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a peculiar neoplasm that is restricted to the sinonasal tract, exhibits features of both a surface-derived and salivary gland carcinoma (particularly adenoid cystic carcinoma), and is associated with high-risk HPV. Given the limited number of published cases, the full clinicopathologic spectrum of this neoplasm is unclear. Here, we present an updated experience of 49 cases. All cases of HMSC were obtained from the authors’ files. Immunohistochemistry for p16, c-kit, and myoepithelial cell markers (S100, actin, calponin, p63, and/or p40) was performed along with RNA in situ hybridization for HPV (type 33-specific as well as a high-risk cocktail). Fluorescence in situ hybridization studies for fusions of MYB, NFIB, and MYBL1 was performed on a subset of cases. Clinical follow-up was obtained from medical records. A total of 49 cases of HMSC were collected. Twenty-eight (57%) were from women and 18 (43%) from men, ranging in age from 28 to 90 years (mean, 54 y). Of 40 cases with detailed staging information, 43% of HMSCs presented with a high T-stage (T3 or T4). Histologically, most grew predominantly as solid nests of basaloid cells exhibiting high mitotic rates and frequent necrosis, with histologic and immunohistochemical evidence of myoepithelial differentiation. Most cases also demonstrated foci of cribriform and/or tubular growth, along with an inconspicuous population of ducts. Thirty-four (69%) cases demonstrated an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa. Less consistent histologic features included squamous differentiation within the invasive tumor (n=6), sarcomatoid transformation (n=5) including overt chondroid differentiation (n=3), and prominent epithelial-myoepithelial carcinoma-like growth (n=3). All cases were positive for p16 by immunostaining and HPV by RNA in situ hybridization. Thirty-three (67%) were positive for HPV 33. No cases tested for MYB, MYBL1, or NFIB gene fusions were positive. In the 38 cases with follow-up data, (mean follow-up, 42 mo) 14 recurred locally and 2 metastasized (lung, finger). There were no regional lymph node metastases, and no tumor-related deaths. HMSC is a distinct sinonasal neoplasm characterized by myoepithelial differentiation, frequent surface epithelial involvement, and the presence of high-risk HPV (especially type 33). Although it classically exhibits a cribriforming pattern that closely resembles adenoid cystic carcinoma, our expanded series highlights a histologic spectrum that is much broader than previously recognized, warranting a change in terminology. HMSC usually presents as a large and destructive sinonasal mass with high-grade histologic features, but it paradoxically behaves in a relatively indolent manner, underscoring the importance of distinguishing HMSC from true adenoid cystic carcinoma, squamous cell carcinoma, and other histologic mimickers.

Activation of the interleukin-6/Janus kinase/STAT3 pathway in pleomorphic adenoma of the parotid gland

The interleukin‐6 (IL‐6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway is of crucial importance in promoting tumorigenesis in several malignant tumors but may also be active in benign tumors, e.g., of pleomorphic adenoma (PA). In this study we characterize the expression of the pathway components with immunohistochemistry and selected mRNAs and microRNAs (miRNAs) regulated by this pathway in isolated duct‐ and myoepithelial cells in PA. 46 PAs were immunostained and 10 of these were used for in situ hybridization (ISH). Six frozen specimens were analyzed using reverse transcription‐polymerase chain reaction (RT‐PCR). Using immunohistochemistry, IL‐6, JAK1, JAK2 and STAT3 were detected significantly more frequently in PA cells than in cells from normal salivary gland tissue. Using RT‐PCR cyclin D1, fibroblast growth factor 2, and p21 were found to be overexpressed while matrix metallopeptidase 9 was detected at low levels in PA compared to normal salivary gland. ISH showed significant overexpression of miR‐181b in PA, while miR‐21 was undetectable in PA and normal tissue. Overexpression of the pathway components and its mRNA and miRNA products provide important clues regarding the growth of PAs. Our findings brings us one step closer to targeted treatment of this tumor entity, although in vitro studies are warranted to confirm this.

Genomic profiling of a combined large cell neuroendocrine carcinoma of the submandibular gland.

A 69-year-old female with no previous medical history presented with a rapidly growing submandibular mass. Fine needle aspiration cytology suggested a small-cell carcinoma and PET-CT showed increased 18-FDG uptake in the submandibular mass as well as in a lung mass. Submandibular resection and selective neck dissection was performed and histopathologic examination revealed a combined large-cell neuroendocrine carcinoma (LCNEC) with a squamous component and without lymph node metastases. Resection of the lung tumor revealed a papillary adenocarcinoma that was morphologically distinctly different from the LCNEC. The patient died of her lung cancer after 19 months without evidence of recurrence of the LCNEC. Genomic profiling of the salivary gland LCNEC revealed a hypodiploid genome predominated by losses of whole chromosomes or chromosome arms involving chromosomes 3p, 4, 7q, 10, 11, 13, 16q and gains of 3q and 16p. In addition, there was a segmental gain of 9p23-p22.3 including the NFIB oncogene. Continued studies of salivary gland LCNEC may provide new knowledge concerning potential diagnostic biomarkers and may ultimately also lead to the identification of new treatment targets for patients with these aggressive carcinomas.

Lacrimal gland ductal carcinomas: Clinical, Morphological and Genetic characterization and implications for targeted treatment.

Ductal carcinomas (DCs) of the lacrimal gland are very rare but aggressive malignancies. We investigated DC of the lacrimal gland for potentially clinically actionable targets in the search for new therapeutic options.

NUT Carcinoma of the Sublingual Gland.

NUT carcinoma (NC) is a recently described, rare and extremely aggressive cancer primarily located to supradiaphragmatic structures and affecting young individuals. NC is characterized by translocations involving the NUT gene on 15q14 with the most common translocation partner gene being BRD4 on 19p13, resulting in the t(15;19)(q14;p13) karyotype. NC is poorly differentiated and is likely to be overlooked and misdiagnosed as poorly differentiated squamous cell carcinoma (SCC) when immunohistochemical evaluation of NUT protein expression is omitted. Previously, NC has been found in the parotid and submandibular glands and we present the first case in the sublingual gland arising in a 40-year-old woman. We discuss the diagnostic considerations for poorly differentiated carcinomas of the salivary glands and advocate the inclusion of NUT immunohistochemistry in this setting. Not only does the NC diagnosis confer a grave prognosis when treated as SCC as illustrated by the present case, but is important for the inclusion of patients in ongoing clinical trials.

Tumors in the parotid are not relatively more often malignant in children than in adults

INTRODUCTION Tumors of the parotid gland in children are rare and very little data has been published regarding the incidence of these tumors. We present a nationwide survey on this topic. METHODS Data regarding benign and malignant tumors in the parotid gland in children from January 1st, 1990 to December 31st, 2005 in Denmark was collected retrospectively from nationwide registries. This generated 61 patients for inclusion in this study. RESULTS 85% of the tumors were benign and the malignant tumors made up the last 15%. The most common of the malignant tumors was the acinic cell carcinoma (n=4) followed by the mucoepidermoid carcinoma (n=3) and adenoid cystic carcinoma (n=2). The overall female-to-male ratio was 1.18, with a ratio of 1.08 and 2.0 in the benign and malignant groups, respectively. At the end of follow-up (August 1st, 2014) two patients had died, one with adenoid cystic carcinoma and one with mucoepidermoid carcinoma. Both patients had perineural invasion and involved resection margins at presentation. The incidence was 0.12 and 0.53 per 100,000 children of the malignant and benign tumors, respectively. CONCLUSION Pleomorphic adenomas were the predominant neoplasm in the parotid gland in children. The most frequent of the malignant tumors was the acinic cell carcinoma, which is in contrast to previous studies. The proportion of malignant-to-benign parotid gland tumors is in contrast to earlier study reports not higher in children than in adults.

ETV6 Gene Rearrangements Characterize a Morphologically Distinct Subset of Sinonasal Low-grade Non–intestinal-type Adenocarcinoma: A Novel Translocation-associated Carcinoma Restricted to the Sinonasal Tract

Low-grade sinonasal adenocarcinomas (low-grade SNACs) of the sinonasal tract comprise a poorly characterized and histologically heterogeneous group of tumors. We describe three cases of a histologically distinct variant of low-grade SNAC characterized by ETV6 gene rearrangements. The patients included 2 women (aged 32 and 88 y) and a man (aged 75 y); all were initially treated with surgery alone. Follow-up ranged from 9 to 170 months with one patient having 2 local recurrences and none experiencing distant or regional metastases. Tumors were composed of cytologically bland columnar and cuboidal eosinophilic tumor cells with basally located nuclei arranged in tubular and tubulotrabecular patterns. Immunohistochemically, CK7, DOG1, GCDFP-15, and SOX10 were positive in all cases, and vimentin was positive in 2 cases. Scattered single cells or small groups of tumor cells were S-100 positive. Only one case had weak, focal expression of GATA3, and mammaglobin was consistently negative. Two cases had ETV6-NTRK3 gene fusions, whereas ETV6 had an unknown fusion partner gene in one case. The highly similar morphology, immunohistochemical profile, and genetics of the presented cases are suggestive of a specific disease. Although translocation-associated adenocarcinomas in the sinonasal tract have previously been described exclusively as salivary-type carcinomas, we present the first type of carcinoma characterized by recurrent genetic rearrangements and distinct phenotype occurring exclusively in the sinonasal tract with no known major salivary gland counterpart. We provisionally designate this tumor ETV6-rearranged low-grade SNAC. Identification of additional cases is necessary to fully appreciate the morphologic and biological spectrum of this disease.

An update on tumors of the lacrimal gland

Lacrimal gland tumors are rare and constitute a wide spectrum of different entities ranging from benign epithelial and lymphoid lesions to high-grade carcinomas, lymphomas, and sarcomas with large differences in prognosis and clinical management. The symptoms and findings of a lacrimal gland lesion are a growing mass at the site of the lacrimal gland, including displacement of the eyeball, decreased motility, diplopia, and ptosis. Pain is the cardinal symptom of an adenoid cystic carcinoma. Radiological findings characteristically include an oval, well-demarcated mass for benign lesions whereas malignant lesions typically display calcifications, destruction of bone, and invasion of adjacent structures. The diagnosis ultimately relies on histology, as does the choice of treatment and the prognosis. In recent years, the understanding of the biology of numerous types of lacrimal gland neoplasia has improved and the choice of treatment has changed accordingly and holds further promise for future targeted therapies. Treatment of benign epithelial lesions is surgical excision whereas carcinomas often require adjuvant radiotherapy and/or chemotherapy. In contrast, the cornerstone in management of lymphoid lesions is chemotherapy, often including a monoclonal antibody. This article presents an update on the clinical, radiological, histological, and molecular features, along with treatment strategies for tumors of the lacrimal gland.

The interleukin-6/Janus kinase/STAT3 pathway in pleomorphic adenoma and carcinoma ex pleomorphic adenoma of the lacrimal gland.

Pleomorphic adenoma (PA) is the most common tumour of the lacrimal gland, but very little is known about its biology. It has a tendency to recur and an ability to transform into the high‐grade malignancy carcinoma ex pleomorphic adenoma (ca‐ex‐PA), which is also largely unexplored. In this study, we examine the expression of the interleukin‐6/Janus kinase/STAT3 (IL‐6/JAK/STAT3) pathway components in PA and ca‐ex‐PA.