Malignancy rates of salivary gland tumors in Greenlandic Inuit comparable to non-endemic populations; epidemiological mapping of salivary gland tumors 1990-2019.

BACKGROUND: Salivary gland tumors are assumed to be predominantly malignant in the Greenlandic Inuit population, but there is limited literature on the subject. We conducted a retrospective cohort study using national registers to describe the histological tumor types, location, incidence, and survival of benign and malignant salivary gland tumors. METHODS: We analyzed data on all Greenlandic Inuit with an epithelial-derived salivary gland tumor from 1990 to 2019. We extracted data from the Central Personal Registry and crossmatched it with the Danish Pathology Data Bank. All specimens were reviewed by a specialized pathologist. We noted patient and histological characteristics, calculated crude and age-adjusted incidence rates, overall survival, and excess mortality. RESULTS: Our study found that 76% of salivary gland tumors in the Greenlandic Inuit population were benign, with pleomorphic adenoma being the most common. Malignant tumors accounted for 24% of cases, with lymphoepithelial carcinoma being the most common type. The most common place of origin for malignant tumors was the parotid gland (71%) and the submandibular gland (15%). The median age of onset for malignant tumors was 47 years. Age-adjusted incidence rates of malignant tumors for men and women were 3.00 and 4.12 per 100,000 person-years, respectively. CONCLUSION: Our findings suggest that the proportion of malignant salivary gland tumors in the Greenlandic Inuit population is similar to other nonendemic populations. Our incidence rates are higher than previously reported, likely due to differences in methodology and definitions of the Inuit population. This study provides valuable insights into the epidemiology of salivary gland tumors in the Greenlandic Inuit population and may have implications for other Inuit populations as well.

Salivary gland carcinoma in Denmark: a national update and follow-up on incidence, histology, and outcome.

PURPOSE: Salivary gland carcinoma is a rare disease and studies on epidemiology and outcome require data collection over many years. The aim of this study is to present an update of incidence rates, anatomical sites, histological subtypes, and survival rates based on the Danish national cohort of salivary gland carcinoma patients. METHODS: Data from all Danish patients with salivary gland carcinoma diagnosed from 1990 to 2015 (n = 1601) were included and analyzed following histological reevaluation and reclassification. Overall, disease-specific, and recurrence-free survival were evaluated. Prognostic factors were analyzed with multivariate Cox Hazard Regression. RESULTS: The study population consisted of 769 men and 832 women, median age 62 years (range 6-102). The most frequent anatomic site was the parotid gland (51.8%). Adenoid cystic carcinoma was the most common subtype (24.7%). The majority had tumor classification T1/T2 (65.3%). The mean crude incidence was 1.2/100.000/year with an increase of 1.5% per year. There was no increase in age-adjusted incidence. The 5-, 10-, and 20-year survival rates were for overall survival 68, 52, and 35%, for disease-specific survival, 77, 69, and 64%, and for recurrence-free survival, 75, 64, and 51%, respectively. Age, high-grade histological subtype, advanced T-classification, cervical lymph node metastases, vascular invasion, and involved surgical margins had significantly negative impact on survival rates. CONCLUSION: The age-adjusted incidence has been stable for a period of 26 years. Multivariate analysis confirmed that histological grade, advanced stage, involved surgical margins and vascular invasion are independent negative prognostic factors. Survival rates were stationary compared to earlier reports.

Sinonasal Undifferentiated Carcinoma (SNUC): From an Entity to Morphologic Pattern and Back Again-A Historical Perspective.

Since the first description of sinonasal undifferentiated carcinoma (SNUC) as a distinctive highly aggressive sinonasal neoplasm with probable origin from the sinonasal mucosa (Schneiderian epithelium), SNUC has been the subject of ongoing study and controversy. In particular, the SNUC category gradually became a "wastebasket" for any undifferentiated or unclassifiable sinonasal malignancy of definite or probable epithelial origin. However, with the availability of more specific and sensitive immunohistochemical antibodies and increasing implementation of novel genetic tools, the historical SNUC category became the subject of progressive subdivision leading to recognition of specific genetically defined, reproducible subtypes. These recently recognized entities are characterized by distinctive genetic aberrations including NUTM1-rearranged carcinoma (NUT carcinoma) and carcinomas associated with inactivation of different members of the SWI/SNF chromatin-remodeling gene complex such as SMARCB1-deficient and less frequently SMARCA4-deficient carcinoma. The ring became almost closed, with recent studies highlighting frequent oncogenic IDH2 mutations in the vast majority of histologically defined SNUCs, with a frequency of 82%. A review of these cases suggests the possibility that "true SNUC" probably represents a distinctive neoplastic disease entity, morphologically, phenotypically, and genetically. This review addresses this topic from a historical perspective, with a focus on recently recognized genetically defined subsets within the SNUC spectrum.

Adenoid cystic carcinomas of the salivary gland, lacrimal gland, and breast are morphologically and genetically similar but have distinct microRNA expression profiles.

Adenoid cystic carcinoma is among the most frequent malignancies in the salivary and lacrimal glands and has a grave prognosis characterized by frequent local recurrences, distant metastases, and tumor-related mortality. Conversely, adenoid cystic carcinoma of the breast is a rare type of triple-negative (estrogen and progesterone receptor, HER2) and basal-like carcinoma, which in contrast to other triple-negative and basal-like breast carcinomas has a very favorable prognosis. Irrespective of site, adenoid cystic carcinoma is characterized by gene fusions involving MYB, MYBL1, and NFIB, and the reason for the different clinical outcomes is unknown. In order to identify the molecular mechanisms underlying the discrepancy in clinical outcome, we characterized the phenotypic profiles, pattern of gene rearrangements, and global microRNA expression profiles of 64 salivary gland, 9 lacrimal gland, and 11 breast adenoid cystic carcinomas. All breast and lacrimal gland adenoid cystic carcinomas had triple-negative and basal-like phenotypes, while salivary gland tumors were indeterminate in 13% of cases. Aberrations in MYB and/or NFIB were found in the majority of cases in all three locations, whereas MYBL1 involvement was restricted to tumors in the salivary gland. Global microRNA expression profiling separated salivary and lacrimal gland adenoid cystic carcinoma from their respective normal glands but could not distinguish normal breast adenoid cystic carcinoma from normal breast tissue. Hierarchical clustering separated adenoid cystic carcinomas of salivary gland origin from those of the breast and placed lacrimal gland carcinomas in between these. Functional annotation of the microRNAs differentially expressed between salivary gland and breast adenoid cystic carcinoma showed these as regulating genes involved in metabolism, signal transduction, and genes involved in other cancers. In conclusion, microRNA dysregulation is the first class of molecules separating adenoid cystic carcinoma according to the site of origin. This highlights a novel venue for exploring the biology of adenoid cystic carcinoma.

Salivary myoepithelial cells: an addendum.

Salivary myoepithelial cells bear particular appendages and are involved in processes that have received incomplete attention in previous reviews. Here, cilia on myoepithelial cells are reviewed as regards substructure, occurrence, detection (electron microscopy, double immunofluorescence together with confocal microscopy), and roles (sensory reception, evolutionary homology, paracrine interaction). Attention is drawn to regressive changes affecting those cells (e.g. accumulation of lipofuscin), possible alterations of their cytoskeleton, internalization of apoptotic bodies and haemosiderin, and role in salivary microcalcification. The ability of differentiated salivary myoepithelial cells to divide is re-examined, particularly its increase in chronic inflammation and under experimental conditions. Caution with regard to histogenetic models of salivary neoplasia is re-emphasized; methodological deficiencies and areas of controversy are outlined; and lines of future research are suggested.

Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: clinical and morphological characterization of six new cases.

AIMS: Human papillomavirus (HPV) is known as causative for squamous cell carcinoma (SCC) of the oropharynx, but is also found not infrequently in carcinomas of the sinonasal tract. Recently, a subset of these carcinomas was recognized to harbour HPV33 and have a significant morphological overlap with adenoid cystic carcinoma (ACC), a rare and aggressive carcinoma originating in the minor salivary glands. Termed 'HPV-related carcinoma with ACC-like features', only nine cases have been reported. To clarify the occurrence of these tumours we screened a large material for the presence of HPV-related ACC-like carcinoma. The identified tumours were characterized immunohistochemically and with fluorescence in-situ hybridization, and clinicopathological information for all cases is presented. METHODS AND RESULTS: Forty-seven candidate cases were screened for presence of HPV. Six cases were identified and genotyped as HPV types 33, 35, and 56. All six cases had areas of dysplastic mucosal lining and showed remarkable heterogeneous morphologies. MYB, MYBL1, and NFIB genes were intact and, interestingly, staining for MYB protein was largely negative in contrast to what was found in ACC. One patient experienced a local recurrence 11 years after initial treatment and the remaining five patients were alive without evidence of disease. CONCLUSION: We report six new cases of HPV-related ACC-like carcinoma and found that, although in a small material, the prognosis for these patients seems more favourable than for ACC. For the distinction between ACC and HPV-related ACC-like carcinoma, p16, MYB immunohistochemistry or investigation of MYB, MYBL1 and NFIB gene status are valuable.

Stationary facial nerve paresis after surgery for recurrent parotid pleomorphic adenoma: a follow-up study of 219 cases in Denmark in the period 1985-2012.

The purpose was to assess degree of permanent facial nerve dysfunction after surgery for recurrent pleomorphic adenoma (RPA) of the parotid gland, including variables that might influence re-operation outcomes. Nationwide retrospective longitudinal cohort study including a questionnaire survey of patients undergoing surgery for RPA. Of 219 living patients, 198 (92 %) responded and 127 (63 %) reported no facial dysfunction. Statistically significant associations were found between number of surgeries and permanent facial nerve dysfunction of all degrees (OR 1.43, 95 % CI 1.16-1.78, p = 0.001). A not significant tendency for females to be associated with worse outcome was found (p = 0.073). Risks of different degrees of paresis after the second-fourth surgeries were found (OR 1.86-2.19, p < 0.05). Our study demonstrates a significant correlation between number of surgeries for RPA of the parotid and severity of facial nerve paresis. This is important when informing and planning treatment of these patients.

Tumors of the sublingual gland: a national clinicopathologic study of 29 cases.

Tumors of the salivary glands are a heterogeneous group of diseases most often originating in the major salivary glands. Only a minor proportion of mainly malignant tumors arise in the sublingual gland. Due to the rarity of sublingual gland tumors (SGTs), little is known about the clinicopathologic characteristics, prognostic factors, and clinical course. We present a large national series of histopathologically revised SGTs from the past 35 years in Denmark with clinicopathologic correlation. Twenty nine cases were identified, of which 96.6 % were malignant and 16/28 (57.1 %) were adenoid cystic carcinomas (ACC). Patient demography was similar to salivary gland tumors in other locations. All fine needle aspiration cytologies (FNACs) interpreted as benign were from ACCs. Metastatic disease was found in 12.5 % of ACCs at diagnosis with one third of all ACC patients having metastases at the end of follow-up. Stage >II and T-stage >2 were significantly associated with shortened disease-specific survival (DSS) (p = 0.005 and <0.001, respectively), whereas perineural invasion and involved margins was not. No parameters were associated with disease-free survival. In conclusion, the majority of SGTs are malignant, most frequently ACC with a high rate of metastatic spread. The diagnostic value of FNAC in SGTs seems inferior to what is found for other major salivary glands. DSS is determined by stage and T-stage and not by histopathological parameters. International collaboration is warranted to confirm and elaborate these findings in larger materials.

Dominant Gene Expression Profiles Define Adenoid Cystic Carcinoma (ACC) from Different Tissues: Validation of a Gene Signature Classifier for Poor Survival in Salivary Gland ACC.

Adenoid cystic carcinoma (ACC) is an aggressive malignancy that most often arises in salivary or lacrimal glands but can also occur in other tissues. We used optimized RNA-sequencing to analyze the transcriptomes of 113 ACC tumor samples from salivary gland, lacrimal gland, breast or skin. ACC tumors from different organs displayed remarkedly similar transcription profiles, and most harbored translocations in the MYB or MYBL1 genes, which encode oncogenic transcription factors that may induce dramatic genetic and epigenetic changes leading to a dominant 'ACC phenotype'. Further analysis of the 56 salivary gland ACC tumors led to the identification of three distinct groups of patients, based on gene expression profiles, including one group with worse survival. We tested whether this new cohort could be used to validate a biomarker developed previously with a different set of 68 ACC tumor samples. Indeed, a 49-gene classifier developed with the earlier cohort correctly identified 98% of the poor survival patients from the new set, and a 14-gene classifier was almost as accurate. These validated biomarkers form a platform to identify and stratify high-risk ACC patients into clinical trials of targeted therapies for sustained clinical response.

Lymphoma of the Uvula: Clinical, Morphological, Histopathological, and Genetic Characterization. A Nationwide Danish Study From 1980 to 2019.

Background: In the head and neck region the uvula is a rare site for extranodal lymphomas to develop. In this national study, we present six cases and provide an overview of the current literature, characterizing the clinical and histopathological features of lymphomas involving this location. Materials and Methods: Clinical information was obtained retrospectively from patient records in a nationwide Danish study covering from 1980 through 2019. In order to validate the diagnoses, uvular tissue specimens were examined histologically and immunohistochemically and if relevant for subtyping, cytogenetic rearrangements were investigated. Results: We present six cases of lymphomas involving the uvula, of which four of the cases were diagnosed with a B-cell lymphoma (two diffuse large B-cell lymphomas, one extranodal marginal zone B-cell lymphoma and one Mantle cell lymphoma), while two were diagnosed with a T-cell lymphoma (one peripheral T-cell lymphoma and one natural killer/T-cell lymphoma). Presenting symptoms included swelling, pain and ulceration of the uvula. Treatment was comprised of radiotherapy and/or chemotherapy, with T-cell lymphomas showing a poorer outcome than B-cell lymphomas. Conclusion: Lymphoma of the uvula is rare, with few case reports being reported in the literature. The most frequent histological subtypes reported are extranodal marginal zone B-cell lymphoma and peripheral T-cell lymphoma. When encountering a swollen, painful and/or ulcerated uvula, the clinician should always consider malignancy as a possible cause. Lymphoma of the uvula is a possible diagnosis and if this is the case, there is a high risk of disseminated disease at the time of diagnosis.

ALK alterations in salivary gland carcinomas.

Salivary gland carcinomas represent a heterogeneous group of poorly characterized head and neck tumors. The purpose of this study was to evaluate ALK gene and protein aberrations in a large, well-characterized cohort of these tumors. A total of 182 salivary gland carcinomas were tested for anaplastic lymphoma kinase (ALK) positivity by immunohistochemistry (IHC) using the cut-off of 10% positive cells. ALK positive tumors were subjected to FISH analysis and followed by hybrid capture-based next generation sequencing (NGS). Of the 182 tumors, 8 were ALK positive by IHC. Further analysis using hybrid capture NGS analysis revealed a novel MYO18A (Exon1-40)-ALK (exon 20-29) gene fusion in one case of intraductal carcinoma. Additional genomic analyses resulted in the detection of inactivating mutations in BRAF and TP53, as well as amplifications of ERBB2 and ALK. ALK rearrangements are a rare entity in salivary gland carcinomas. We identified a potentially targetable novel ALK fusion in an intraductal carcinoma of minor salivary glands.

Trends in the Management of Non-Vestibular Skull Base and Intracranial Schwannomas.

The aim of this review is to analyze the latest trends in the management of non-vestibular skull base and intracranial schwannomas in order to optimize tumor control and quality of life. Non-vestibular cranial nerve schwannomas are rare lesions, representing 5-10% of cranial nerve schwannomas. Management decisions should be individualized depending on tumor size, location and associated functional deficits. Generally, large sized schwannomas exerting significant mass effect with increased intracranial pressure are treated surgically. In some cases, even after optimal skull base resection, it is not possible to achieve a gross total resection because tumor location and extent and/or to reduce morbidity. Thus, subtotal resection followed by stereotactic radiosurgery or fractioned radiotherapy offers an alternative approach. In certain cases, stereotactic radiosurgery or radiotherapy alone achieves good tumor control rates and less morbidity to gross total resection. Finally, given the slow growth rate of most of these tumors, observation with periodic radiographic follow-up approach is also a reasonable alternative for small tumors with few, if any, symptoms.

Natural history of recurrent pleomorphic adenoma: implications on management.

BACKGROUND: Treating recurrent pleomorphic adenoma (RPA) aims to reduce risk of malignant transformation (MT) while avoiding facial nerve injury. Our objective was to systematically investigate this natural history of RPA and address the current rational for its treatment. METHODS: The follow-up data of two nationwide series of PA was pooled with a focus on risk of MT and analyzed against the literature. RESULTS: The combined nationwide data (n = 9003 PA patients) showed 3.1% with first recurrence of which 6.2% were malignant. In the literature first RPA rate was >7% at 20 years follow-up. MT occurred in 0% to 7%, and facial nerve damage increased from with each surgery 3% to 16% at first RPA to 18% to 30% at second RPA. CONCLUSIONS: RPA showed a characteristic course with surgery being unreliable and damage to the facial nerve. The risk of MT was low. This might give flexibility towards a more conservative approach of management.

Gamma Knife Radiosurgery for Uveal Melanoma: A Retrospective Review of Clinical Complications in a Tertiary Referral Center.

INTRODUCTION: Gamma knife radiosurgery (GKR) has shown promising results in the treatment of intraocular uveal melanoma (UM) in terms of local tumor control. However, GKR is not free from potentially sight-threatening side effects, including cataract, dry eye disease, vitreous hemorrhage, radiation retinopathy (RR), radiation maculopathy (RM), optic neuropathy, and neovascular glaucoma. The aim of this paper is to report our 20-year experience in UM management with GKR focusing on the rate of clinical treatment-induced complications. METHODS: Single-center, retrospective, observational study, including all patients with UM treated at the Ocular Oncology and Uveitis Service, in the Department of Ophthalmology of the San Raffaele Scientific Institute, Milan from September 1993 to September 2018. Clinical charts comprised complete ophthalmological examination with measurement of best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure measurement, gonioscopy, and indirect ophthalmoscopy at each visit. B-scan ultrasound (Aviso S, 10 MHz probe; Paris, France), optical coherence tomography (Heidelberg Spectralis; Heidelberg Engineering, Heidelberg, Germany), retinography, and fundus fluorescein angiography (standard or ultra-widefield [UWF; California, Optos, Dunfermline, Scotland, UK]) were performed aiding in the diagnosis of complications. RESULTS: Overall, 194 patients (100 males, 51.6%) were reviewed. The median age at the time of the treatment was 65 years (range 27-89) and all participants were Caucasian. In 185 eyes (95.4%), the tumor was primarily located at the choroid. The median follow-up was 57.6 months; radiation-induced complications were found in 145 eyes (74.7%). Radiation-induced cataract and RR were the most frequent events, with a relative incidence of 41.2 and 34.5%, respectively, followed by neovascular glaucoma (27.3%), optic neuropathy (18.6%), RM (11.4%), vitreous hemorrhage (14.4%), phthisis bulbi (7.7%), hyphema (0.5%), and corneal melting (0.5%). The shorter onset of side effects involved the optic nerve (median 14.9 months) and the macula (median 13.7 months). CONCLUSION: Despite modern and advanced strategies introduced to limit GKR side effects, cataract and RR still represent a serious limitation of this treatment. Incidence of RR was higher in our cohort compared to other reports, probably due to increased diagnosis rate permitted by UWF retinal imaging.

Lymphoma of the Sublingual Gland: Clinical, Morphological, Histopathological, and Genetic Characterization.

Background: Lymphoma of the sublingual gland is rare, representing 1% of all salivary gland lymphomas. In this case report, we present three new cases and compare them to previously published cases, with the aim of characterizing the clinical, morphological, histopathological, and genetic features of this type of malignancy. Materials and Methods: We provide a clinical description of three cases along with a characterization of the microscopic features, including morphology, and immunohistochemistry. In addition, we analysed possible cytogenetic rearrangements with the use of fluorescence in situ hybridization (FISH). Results: Case 1: A 61-year-old male presenting with a painless swelling of the floor of the mouth diagnosed as extranodal marginal zone lymphoma (EMZL) of the left sublingual gland. The patient is alive with no evidence of disease after his fourth treatment regimen following several relapses. Case 2: A 68-year-old female with a prior history of mantle cell lymphoma (MCL) presenting with a tender swelling of the left sublingual gland as well as the right submandibular gland. The lesions were diagnosed as relapsing MCL. The patient died of unrelated causes after 18 months of treatment. Case 3: A 75-year-old female presenting with a swelling of the floor of the mouth diagnosed as follicular lymphoma (FL) of the left sublingual gland. The patient received chemotherapy along with radiotherapy and was still alive 10 years after the diagnosis. Conclusion: The three cases of sublingual gland lymphomas presented in this case report resemble lymphomas of other major salivary glands. The clinician should be aware of this type of malignancy and that the clinical presentation may not differ from benign lesions or other more common malignancies in this location.

Association of programmed death ligand 1 expression with prognosis among patients with ten uncommon advanced cancers.

AIM: PD-L1 expression and high levels of microsatellite instability (MSI-H) may predict response to checkpoint inhibitors, but their prevalence and prognostic value are unknown in many cancers. METHODS: We retrospectively evaluated PD-L1 combined positive score (CPS) and MSI-H and their association with clinical outcomes among patients with ten advanced uncommon cancers. RESULTS: 398 of 426 patients (93%) had a valid PD-L1 result; most (242; 61%) had CPS ≥1. Prevalence of MSI-H tumors was 8/360. Median overall survival was shorter among patients with PD-L1 CPS ≥1 tumors after first-line treatment (23.0 vs 39.7 months, p = 0.014). CONCLUSION: PD-L1 was commonly expressed in solid tumors, and CPS ≥1 was associated with shorter overall survival. Prevalence of MSI-H was low.

Global microRNA profiling of metastatic conjunctival melanoma.

This study aimed to investigate the microRNA (miRNA) profile in primary tumors from conjunctival melanoma with and without subsequent metastatic spread along with their coupled distant metastases to identify miRNAs likely to be involved in metastatic progression. This observational study included 13 patients with metastatic conjunctival melanoma (follow-up: 1-39 years) treated at a Danish referral center. Twenty-five patients with nonmetastatic conjunctival melanoma (follow-up: 5-17 years) were included for comparison. Global miRNA profiling was performed with the Affymetrix GeneChip 4.1 microarray. Taqman qPCR arrays were used for validation. Significant differentially expressed miRNAs were defined as having a false discovery rate of less than 0.05. Primary conjunctival melanoma with and without subsequent metastatic spread clustered separately according to miRNA expression, and 15 miRNAs were found to have significant differential expression. Six miRNAs (hsa-miR-4528, hsa-miR-1270, hsa-miR-1290, hsa-mir-548f-4, hsa-mir-4278, and hsa-miR-34a-3p) were downregulated and nine miRNAs were upregulated (hsa-mir-575, hsa-miR-527, hsa-miR-518a-5p, hsa-miR-6759-5p, hsa-miR-8078, hsa-mir-4501, hsa-mir-622, hsa-mir-4698, and hsa-mir-4654) in primary conjunctival melanoma with subsequent metastatic spread. A comparison of primary conjunctival melanoma with their pair-matched metastases identified six significant differentially expressed miRNAs (hsa-miR-1246 and hsa-miR-302d-5p, hsa-mir-6084, hsa-miR-184, hsa-mir-658, and hsa-mir-4427). qPCR confirmed downregulation of hsa-miR-184 in the distant metastases when compared with the corresponding primary tumor. Primary conjunctival melanoma with and without subsequent metastatic spread separated clearly on the miRNA level when profiled with microarray-based methods. qPCR was able to replicate expression levels of one miRNA (hsa-miR-184) that was downregulated in metastases when compared with corresponding primary tumors.

Lymphomas of the head and neck region: an update.

The field of haematopathology is rapidly evolving and for the non-specialized pathologist receiving a specimen with the possibility of a lymphoid malignancy may be a daunting experience. The coincidence of the publication, in 2017, of the WHO monographies on head and neck and haematopoietic and lymphoid tumours prompted us to write this review. Although not substantially different from lymphomas elsewhere, lymphomas presenting in this region pose some specific problems and these are central to the review. In addition, differences in subtype frequency and morphological variations within the same entity are discussed. The difficulty in diagnosis related to some specimens led us to briefly mention common subtypes of systemic lymphomas presenting in the head and neck region.

CAIX and pax-8 Commonly Immunoreactive in Endolymphatic Sac Tumors: A Clinicopathologic Study of 26 Cases with Differential Considerations for Metastatic Renal Cell Carcinoma in von Hippel-Lindau Patients.

Endolymphatic sac tumors (ELSTs) are rare, slowly growing temporal bone neoplasms which show a high association with von Hippel-Lindau (VHL) syndrome. The immunohistochemistry evaluation of these papillary-cystic neoplasms frequently raises the differential diagnosis with renal cell carcinoma, among other metastatic neoplasms, whether in VHL patients or not. A cohort of 26 patients with ELSTs were evaluated for histologic features, immunohistochemistry findings, and association with VHL. Standard immunohistochemistry evaluation was performed. Sixteen females and 10 males ranging in age from 10 to 69 years (mean 44; VHL mean: 32) at initial presentation, comprised the cohort of patients. Most (86%) experienced hearing changes or inner ear symptoms (vertigo, dizziness), with an average duration of symptoms for 39 months (range 2-240 months). The tumors were an average of 2.9 cm (range 0.4-8 cm), with 14 left, 11 right sided and one bilateral tumor. Nine patients had documented VHL, with 3 patients having a concurrent or subsequent clear cell renal cell carcinoma. Patients were followed an average of 6.2 years (available in 24 patients): 19 alive without disease, 7.5 years; 2 dead without disease, 1.2 years; and 3 alive with disease, 3.1 years. The neoplastic cells show the following immunohistochemistry findings: AE1/AE3, EMA, CK7, CAIX, GLUT1, VEGF: 100% of cases tested were positive; pax-8: 85% of cases positive; CD10 and RCC: 0% of cases reactive. Based on this cohort of 26 patients with ELST, 9 of whom had VHL, the strong pax-8 and CAIX should be used in conjunction with negative CD10 and RCC to help exclude a metastatic renal cell carcinoma. As CAIX is an enzyme overexpressed in hypoxia and hypoxia inducible factor is what VHL protein regulates, this is an expected, although previously unreported finding. Whether part of VHL or not, VHL mutations may be a somatic rather than germline finding in the tumors, a possible further explanation for the CAIX reaction.