Factors affecting the variable outcomes of juvenile nasopharyngeal angiofibroma

Background Juvenile Nasopharyngeal Angiofibroma (JNA) is a rare, benign tumour affecting adolescent males. Due to its capability to erode bone, JNA can be accompanied by life-threatening complications when growing into the cranium. The etiology of JNA is unknown, as are the factors determing the variable growth patterns of individual tumours. The treatment of choice for JNA is surgery, but high recurrence rates or persistent growth are charasteristic. Aims The aim of this study was to elucidate factors determing the variable outcomes of JNA. For this purpose the various surgical techniques used to resect JNA during the past 40 years at the Helsinki University Central Hospital (HUCH) were investigated, immunohistochemistry was performed and the gene copy number and mRNA expression data of two phenotypically different JNA tumours were combined to seek for processes putatively determining their growth pattern. Methods Retrospective clinicopathological data of all JNA patients diagnosed and treated, during the years 1970-2011, were reviewed. By immunohistochemistry, we investigated the cellular distribution and expression levels of C-KIT, C-MYC, BMI-1, GLUT-1, tenascin-C, syndecan-1, syndecan-2 and SYK in JNA samples, in order to find their possible correlations with clinicopathological factors. Comparative genomic hybridisation and gene expression analyses were performed for two phenotypically different tumour samples to investigate the possible processes leading to more aggressive growth. A gene ontology enrichment analysis for the in silico translated proteins of genes with altered gene expression status was performed to detect the categories with enrichments. Results The primary recurrence rate was 37% and correlated with the surgical approach used, transpalatal approach linked with higher risk of recurrence, vascularity of the tumour and young age of the patient. Contrary to previous reports, C-KIT was expressed in both stromal and endothelial cells of JNA samples and was more prominent in slit-like vessels. A correlation between its endothelial expression and cellular density of the tumour was found. Frequent stromal tenascin-C expression had a strong correlation with vessel density and higher tumour stage. When present, endothelial GLUT-1 expression correlated with higher tumour stage. SYK expression was found to correlate with lower tumour stage. Between the low and high stage JNA tumours studied, 1245 genes showed at least a two-fold- change in their expression. The corresponding proteins of these transcripts were enriched in different biological processes, e.g., hypoxia in the low stage tumour and signal transduction activity in the high stage tumour. Conclusions The type of surgical approach seemed crucial for the outcome. Other clinical factors affecting the recurrence rate were young age of the patient and vascular density of the tumour. In selective cases of JNA, we could thus carefully recommend the consideration of antiangiogenic treatment. Based on our finding of protein expressions, we suggest that at least C-KIT, tenascin-C, GLUT-1 and SYK might be substantial in the growth of JNA by having an effect on tumour cellularity, vessel density and the stage of the tumour. Based on our result of GLUT-1 positivity correlating with higher tumour stage, we suggest that JNAs are not likely to be vascular malformations. Although we were able to identify gene expression changes that relate to particular biological processes, the assessing of clinically relevant molecular profiles of JNA still requires further characterization. In the future, combinating molecular profiling data from several studies will be useful to better understand the molecular background of this rare tumour.Nenänielun juveniili angiofibrooma (engl. Juvenile Nasopharyngeal Angiofibroma, JNA) on pääasiassa nuorten miesten harvinainen, histologisesti hyvänlaatuinen kasvain. JNA kykenee kasvaessaan syövyttämään luuta, mikä saattaa kallonpohjan läpi kasvavien kasvainten tapauksessa johtaa henkeä uhkaaviin komplikaatioihin. Sekä JNA:n syntyyn, että vaihtelevaan kasvutapaan johtavat tekijät ovat epäselviä. Suositeltava hoitomuoto on kasvaimen kirurginen poisto, mutta uusiutuminen ja persistoiva kasvu ovat JNA:lle tyypillisiä. Valikoiduissa tapauksissa myös sädehoitoa voidaan harkita, jos kasvain on laajalle levinnyt, sijaitsee hankalassa paikassa tai uusintaleikkauksia on jo useita. Mahdollisten ennustavien tekijöiden löytäminen edellyttää tunnettujen kasvainten kasvu- ja verisuonikasvutekijöiden tutkimista myös JNA-kasvaimissa. Pyrimme löytämään sellaisia tekijöitä ja tapahtumasarjoja, jotka olisivat keskeisiä JNA:n lopputuleman kannalta. Selvitimme sairaalassamme 40 vuoden aikana käytetyt erilaiset kirurgiset leikkaustavat ja näiden vaikutuksen hoitotulokseen. Immunohistokemiallisin menetelmin tutkimme tunnettujen kasvainten kasvuun ja verisuonten syntyyn vaikuttavien proteiinien ilmentymistä JNA-kudoksissa löytääksemme mahdollisia riippuvuussuhteita kliinispatologisiin tekijöihin. Vertailevaa genomista hybridisaatiota (engl. comparative genomic hybridisation) ja geenien ilmentymisanalyyseja käytettiin kahden fenotyypiltään poikkeavan JNA-kasvaimen yhteydessä, tarkoituksena löytää mahdollisia aggressiivisempaan kasvuun johtavia tapahtumasarjoja. Kaikki 27 potilasta olivat miehiä ja keski-ikä oli 17 vuotta. Käytettyjä leikkaustapoja oli useita, joista suulaen läpi suuntautuva leikkaus oli tässä aineistossa yleisin. Viime vuosina myös useampia muita leikkaustapoja oli otettu käyttöön, näiden joukossa endoskooppinen leikkaus. Primaarinen uusiutuminen tapahtui 37% tapauksesssa ja sen havaittiin olevan yhteydessä käytettyyn leikkaustapaan, kasvaimen verisuonitiheyteen, sekä potilaan matalaan ikään. Tähän perustuen voisimme varovaisesti suositella verisuontenkasvua estävien lääkkeiden harkitsemista tiettyjen valikoitujen tapausten yhteydessä. Poiketen aikaisemmista tuloksista, havaitsimme C-KIT:n ilmentyvät sekä strooman, että verisuonten endoteelin soluissa. Endoteelisoluissa ilmentyvän C-KIT:n ja kasvaimen solutiheyden välillä havaittiin tilastollisesti merkittävä riippuvuussuhde. Tenascin-C ilmentyi strooman soluissa usein ja näytti olevan riippuvuussuhteessa niin kasvaimen verisuonitiheyden kuin kasvaimen levinneisyysasteenkin kanssa. Ilmentyessään endoteelisoluissa, GLUT-1 näytti olevan riippuvuussuhteessa korkeamman kasvaimen levinneisyysluokan kanssa. Tämän perusteella pidämme epärodennäköisenä, että JNA:t, tai edes osa niistä, olisivat verisuoniepämuodostumia. SYK:n ilmentyminen oli riippuvuussuhteessa matalamman kasvaimen levinneisyysluokan kanssa. Matalaa ja korkeaa levinneisyysluokkaa edustavien JNA kasvainten välillä löysimme 1245 geeniä, joiden ilmentymisen tasojen välillä oli vähintään kaksinkertainen ero. Näitä geenejä vastaavat kopio nukleiinihappojaksot (engl. transcript) olivat rikastuneet erilaisiin tapahtumasarjoihin. Kirurgisen leikkaustavan valinta näyttäisi keskeiseltä hoidon lopputuloksen kannalta ja uusiutumisen riskin pienentämiseksi myös viimeaikainen erilaisten hoitomuotojen kehitys tulisi mahdollisuuksien mukaan ottaa huomioon hoitoa suunniteltaessa. Tuloksemme erilaisten proteiinien ilmentymistä koskien ovat viitteellisiä sen suhteen, että ainakin C-KIT, tenascin-C, GLUT-1 ja SYK voisivat olla oleellisia JNA:n kasvun kannalta, vaikuttaessaan kasvaimen solukkuuteen, verisuonitiheyteen, sekä kasvaimen levinneisyyteen. Vaikka kahden kasvutavaltaan erilaisen JNA-kasvaimen toisistaan poikkeavien geenien ilmentymistasojen perusteella onnistuimmekin jo löytämään joitain kasvun kannalta mahdollisesti keskeisiä tapahtumasarjoja, kliinisesti merkittävien molekulaaristen profiilien selvittäminen vaatii vielä lisää tutkimuksia. Johtuen taudin harvinaisuudesta tulee useiden tehtyjen tutkimuksien avulla saavutetun tiedon yhdistäminen tulevaisuudessa todennäköisesti olemaan hyödyllistä, kun selvitetään kasvaimen molekulaarista taustaa

Targeted Treatment With Radio Frequency Ablation for Lingual Tonsil

Objectives:Benign enlargement of the lingual tonsils due to various causes may cause symptoms that warrant treatment. Conventional lingual tonsillectomy remains a challenging procedure, and there is no established standard procedure. We aimed to review the patients receiving different methods of lingual tonsil surgery for various indications at our institute.Methods:Retrospective clinical data on all patients with an ablative operation of the tongue base during the 8-year period between 2007 and 2014 at the Helsinki University Hospital, Helsinki, Finland, were reviewed. The larger cohort comprised 35 patients, of whom 26 were men (74%). Ten patients had undergone solely lingual tonsil radio frequency ablation (LTRFA). The minimum follow-up time for all patients was 2 years.Results:Of the 10 patients, 5 patients with LTRFA had been operated on because of symptomatic lingual tonsil hypertrophy and 5 because of periodic fever associated with possible lingual tonsil involvement. In 2 of the 5 patients with periodic fever, the fever cycles ended after the operation. Of the 5 patients, 3 patients with symptomatic lingual tonsil hypertrophy have been non-symptomatic after 1 to 3 treatment sessions. The last 2 patients continue to have persistent symptoms. There were no major complications.Conclusions:Development of new approaches for the management of various lingual tonsil conditions is warranted. Lingual tonsil volume reduction by LTRFA seems to be a treatment alternative with low morbidity but with limited curative effect only.Peer reviewe

Accuracy of preoperative MRI to assess lateral neck metastases in papillary thyroid carcinoma

Primary treatment of papillary thyroid carcinoma (PTC) with lateral lymph node metastasis is surgery, but the extent of lateral neck dissection remains undefined. Preoperative imaging is used to guide the extent of surgery, although its sensitivity and specificity for defining the number and level of affected lymph nodes on the lateral neck is relatively modest. Our aim was to assess the role of preoperative magnetic resonance imaging (MRI) in predicting the requisite levels of neck dissection in patients with regionally metastatic PTC, with a focus on Levels II and V. All patients with PTC and lateral neck metastasis who had undergone neck dissection at the Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland from 2013 to 2016 and had a preoperative MRI available were retrospectively reviewed. A head and neck radiologist re-evaluated all MRIs, and the imaging findings were compared with histopathology after neck dissection. In the cohort of 39 patients, preoperative MRI showed concordance with histopathology for Levels II and V as follows: sensitivity of 94 and 67%, specificity of 20 and 91%, positive predictive value of 56 and 75%, and negative predictive value of 75 and 87%, respectively. In PTC, MRI demonstrated fairly high specificity and negative predictive value for Level V metastasis, and future studies are needed to verify our results to omit prophylactic dissection of this level. Routine dissection of Level II in patients with regionally metastatic PTC needs to be considered, as MRI showed low specificity.Peer reviewe

Different toll-like receptor expression patterns in progression toward cancer

Non peer reviewe

Association of BMI-1 and p16 as prognostic factors for head and neck carcinomas

Conclusions BMI-1 is an upstream repressor of tumor suppressor p16 and their inverse expression patterns have been linked with patient survival in OPSCC. In this material only p16 remained a relevant prognostic marker in OPSCC. Objectives HNSCC tumors carry variable phenotypes and clinical outcomes depending on their anatomical location. In OPSCC, expression of tumor suppressor p16 is used as a surrogate marker of HPV infection and has prognostic value. There are no good prognostic biomarkers for HNSCC tumors of other anatomical locations. Aim To study the expression patterns of p16 and BMI-1 in not only oropharyngeal but also oral, hypopharyngeal, and laryngeal squamous cell carcinomas and to clarify their putative connections with clinical parameters, survival, and each other. Method Hospital records on 130 patients (59 OPSCC, 18 OSCC, 20 HPSCC, and 33 LSCC) diagnosed between 1997-2008 at the Helsinki University Hospital, Finland, were reviewed. BMI-1 and p16 expressions were studied by immunohistochemistry. Results Sixty-eight per cent of OPSCC expressed p16 and expression correlated with lower age, lower T- and higher N-category, and with improved OS and DFS. BMI-1 expression was most prevalent in OPSCC and LSCC, but had no clinical correlations. No correlation between p16 and BMI-1 expression was found.Peer reviewe

Genetic and Epigenetic Characteristics of Inflammatory Bowel Disease–Associated Colorectal Cancer

doi: 10.1053/j.gastro.2021.04.042Background & Aims Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder associated with an elevated risk of colorectal cancer (CRC). IBD-associated CRC (IBD-CRC) may represent a distinct pathway of tumorigenesis compared to sporadic CRC (sCRC). Our aim was to comprehensively characterize IBD-associated tumorigenesis integrating multiple high-throughput approaches, and to compare the results with in-house data sets from sCRCs. Methods Whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry were performed using fresh-frozen and formalin-fixed tissue samples of tumor and corresponding normal tissues from 31 patients with IBD-CRC. Results Transcriptome-based tumor subtyping revealed the complete absence of canonical epithelial tumor subtype associated with WNT signaling in IBD-CRCs, dominated instead by mesenchymal stroma-rich subtype. Negative WNT regulators AXIN2 and RNF43 were strongly down-regulated in IBD-CRCs and chromosomal gains at HNF4A, a negative regulator of WNT-induced epithelial–mesenchymal transition (EMT), were less frequent compared to sCRCs. Enrichment of hypomethylation at HNF4α binding sites was detected solely in sCRC genomes. PIGR and OSMR involved in mucosal immunity were dysregulated via epigenetic modifications in IBD-CRCs. Genome-wide analysis showed significant enrichment of noncoding mutations to 5′untranslated region of TP53 in IBD-CRCs. As reported previously, somatic mutations in APC and KRAS were less frequent in IBD-CRCs compared to sCRCs. Conclusions Distinct mechanisms of WNT pathway dysregulation skew IBD-CRCs toward mesenchymal tumor subtype, which may affect prognosis and treatment options. Increased OSMR signaling may favor the establishment of mesenchymal tumors in patients with IBD.BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder associated with an elevated risk of colorectal cancer (CRC). IBD-associated CRC (IBD-CRC) may represent a distinct pathway of tumorigenesis compared to sporadic CRC (sCRC). Our aim was to comprehensively characterize IBD-associated tumorigenesis integrating multiple high-throughput approaches, and to compare the results with in-house data sets from sCRCs. METHODS: Whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry were performed using fresh-frozen and formalin-fixed tissue samples of tumor and corresponding normal tissues from 31 patients with IBD-CRC. RESULTS: Transcriptome-based tumor subtyping revealed the complete absence of canonical epithelial tumor subtype associated with WNT signaling in IBD-CRCs, dominated instead by mesenchymal stroma-rich subtype. Negative WNT regulators AXIN2 and RNF43 were strongly down-regulated in IBD-CRCs and chromosomal gains at HNF4A, a negative regulator of WNTinduced epithelial-mesenchymal transition (EMT), were less frequent compared to sCRCs. Enrichment of hypomethylation at HNF4 alpha binding sites was detected solely in sCRC genomes. PIGR and OSMR involved in mucosal immunity were dysregulated via epigenetic modifications in IBD-CRCs. Genome-wide analysis showed significant enrichment of noncoding mutations to 50 untranslated region of TP53 in IBD-CRCs. As reported previously, somatic mutations in APC and KRAS were less frequent in IBD-CRCs compared to sCRCs. CONCLUSIONS: Distinct mechanisms of WNT pathway dysregulation skew IBD-CRCs toward mesenchymal tumor subtype, which may affect prognosis and treatment options. Increased OSMR signaling may favor the establishment of mesenchymal tumors in patients with IBD.Peer reviewe