Karl Götte

Hereditary hemorrhagic telangiectasia: an update on clinical manifestations and diagnostic measures

ZusammenfassungDie hereditäre hämorrhagische Teleangiektasie (HHT), auch als Morbus Rendu-Osler-Weber bekannt, ist eine autosomal-dominant vererbte Erkrankung des Gefäßbindegewebes. Die Erkrankung wird charakterisiert durch die klassische Trias bestehend aus (muko-)kutanen Teleangiektasien, arteriovenösen Malformationen mit rezidivierender Epistaxis und Hämorrhagien sowie der Heredität. Eine Vielzahl unterschiedlicher klinischer Manifestationsformen der HHT sind beschrieben worden. In mehr als 90% der Fälle stellt die Epistaxis das klinische Erstsymptom dar, wodurch Hals-Nasen-Ohrenärzten eine wichtige Schlüsselrolle in der Diagnosestellung und der Behandlung der HHT zukommt. Trotz neuester diagnostischer und therapeutischer Entwicklungen ist eine Heilung dieser, den Betreffenden in seiner Lebensqualität oft einschränkenden Erkrankung nicht möglich. Außer der Nase sind vor allem die Haut, die Lunge, das Hirn, die Leber und der Gastrointestinaltrakt von arterio-venösen Malformationen (AVM) befallen. Die Entstehung der HHT wird im wesentlichen Mutationen zweier Gene zugeschrieben. Zum einen handelt es sich hierbei um Endoglin (ENG) auf Chromosom 9q33-q34 und activin-receptor like kinase (ALK1) auf Chromosom 12q13. Mutationen von Endoglin werden dem HHT Typ 1 zugeschrieben mit einer Inzidenz von bis zu 40% für pulmonale arteriovenöse Malformationen (AVM). Mutationen von ALK1 entsprechen dem HHT Typ 2 mit einer Inzidenz von bis zu 14% für pulmonale AVM. Diese Arbeit dient zum besseren Verständnis der Komplexität der HHT-Erkrankung, wobei anhand einer Übersicht zur aktuellen Literatur vor allem ein Schwerpunkt auf die klinischen Manifestationsformen, die Molekulargenetik und die Diagnosemöglichkeiten gelegt werden soll. Therapeutische Optionen in der Behandlung der HHT sind hier bewusst nicht erwähnt worden, da sie Gegenstand einer weiteren Arbeit sind. Dadurch, dass die HHT häufiger vorkommt als vermutet und eine weite Bandbreite klinischer Manifestationen aufweisen kann, stellt sie für viele Subspezialisierungen eine enorme Herausforderung dar, die ein eingehendes interdisziplinäres diagnostisches Screening in der Behandlung verlangt.SummaryHereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is an autosomal dominant disorder of the fibrovascular tissue. It is characterized by the classic triad of (muco-)cutaneous telangiectases, arteriovenous malformations with recurrent epistaxis and hemorrhages, and inheritance. A wide variety of clinical manifestations in HHT have been described. In more than 90% of the patients, nosebleeds are the first predominant symptom, therefore ENT physicians often play a key role as far as diagnosis and management of the disease are concerned. In spite of recent diagnostic and therapeutic progress, a cure for this often burdening and handicapping disease is still not available. Apart from affecting the nose, arteriovenous malformations (AVMs) may also affect the skin, lungs, brain, liver and gastrointestinal tract. The two known genes that are implicated in HHT are endoglin (ENG) located on chromosome 9q33-q34 and activin-receptor-like kinase (ALK1) located on chromosome 12q13. Mutations of ENG are observed in HHT type 1 with an incidence up to 40% for pulmonary AVMs, whereas mutations of ALK1 are observed in HHT type 2 with an incidence of only 14% for pulmonary AVMs, which clinically distinguishes these two types of mutation. The emphasis of this paper is mainly on the clinical manifestation, molecular genetics and diagnosis of HHT, taking account of current literature on HHT in order to better understand the complexity of the disease. Recent therapeutic options in the treatment of HHT have been omitted from this paper as they are subject of a following paper. HHT is more common than previously thought and shows a broad range of different clinical organ manifestations that can be sources of substantial morbidity and mortality, making HHT a continuing challenge for many sub-specialties where interdisciplinary diagnostic screening is mandatory in the management of the disease.

Serum levels of vascular endothelial growth factor in patients with head and neck cancer

Abstract Angiogenesis is now considered to be crucial for tumor growth and metastasis. In several tumors, microvascular density has been shown to be correlated with metastasis and aggressiveness. Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific mitogen, which is induced by hypoxia and is angiogenic in vivo. VEGF has been identified in a wide variety of malignancies including head and neck squamous cell carcinomas (HNSCC). We investigated the circulating level of VEGF in sera from patients with various head and neck squamous cell carcinomas (n = 71) as well as from healthy normal controls (n = 47). Serum VEGF concentrations were determined as serum immunoreactivity by using a quantitative sandwich enzyme immunoassay technique. For statistical analysis, the Wilcoxon 2-sample test and Kruskal-Wallis test were performed. The majority of the patients with HNSCC were found to have high concentrations of serum VEGF. The levels of VEGF in the sera of patients with cancer ranged from below the detection limit to 937.1 pg/ml (mean, 144.5 pg/ml). In contrast, the VEGF serum levels in 47 healthy individuals ranged from below the detection limit to 168.1 pg/ml (mean, 32.7 pg/ml), VEGF serum concentration being significantly higher in HNSCC patients (P = < 0.001). These findings indicate that a positive angiogenesis regulator such as VEGF might function as an endocrine growth factor, particularly for solid HNSCC tumors and may be a useful marker for clinical monitoring.

Topical Estrogens Combined with Argon Plasma Coagulation in the Management of Epistaxis in Hereditary Hemorrhagic Telangiectasia

The aim of this study was to assess the value of topically applied estrogens in patients with hereditary hemorrhagic telangiectasia. Twenty-six patients with this disorder were treated with argon plasma coagulation and randomized into 2 groups: group A, which had postoperative application of estriol ointment (n = 14), and group B, which had postoperative application of dexpanthenol ointment (n = 12). Over a period of 12 months, the frequency and intensity of bleeding, the patients satisfaction, and the success of the treatment were evaluated with a questionnaire. Before the operation, more than 90% of the patients in both groups complained of daily episodes of epistaxis. Twelve months after treatment, the frequency and intensity of bleeding had significantly decreased in group A as compared to group B. Of the patients in group A, 93% were satisfied with the treatment. Of the patients in group B, only 42% were satisfied with the treatment. In both groups, more than 90% of the patients were willing to undergo the same treatment again. The combined treatment approach with argon plasma coagulation and topical estriol enables us to significantly prolong the hemorrhage-free interval.

Expression of basic fibroblast growth factor protein and its down-regulation by interferons in head and neck cancer

Angiogenesis is crucial for tumor growth and metastasis. In several tumors, microvascular density has been shown to correlate with metastasis and aggressiveness. Basic fibroblast growth factor (bFGF) has potent angiogenic activity and has been identified in a wide variety of malignancies including head and neck squamous cell carcinomas (HNSCC).

Intratumoral genomic heterogeneity in advanced head and neck cancer detected by comparative genomic hybridization

Little is known about the extent of intratumoral genetic heterogeneity in head and neck squamous cell carcinoma (HNSCC). We therefore examined 79 stage III and IV primary HNSCCs (P) and matched lymph node metastases (M) for over- and underrepresentation of specific chromosome regions by comparative genomic hybridization (CGH). The overall ratio of gains and losses was higher in metastases than in primary tumors (4/1 vs. 2.5/1). Gains of 3q (78.1% P vs. 87.5% M) and 11q (78.1% P vs. 62.5% M) and deletions of 3p (43.8% P vs. 34.4% M) and 9p (31.3% P vs. 15.6% M) were most frequently detected. The highest rate of intratumoral discordance was observed for primary tumors and corresponding metastases (32.8%) compared with matched pairs of two metastases (26.5%) and of two anatomically distinct sides of one primary tumor (24.3%). Furthermore, the discordance rate was dependent on the primary tumor site (oral cavity 49.2%, oropharynx 31%, hypopharynx 30.3%, and larynx 27.3%). In some tumors, the extent of genomic discordance argues against a monoclonal origin. In conclusion, we found a high individual variation of intratumoral genomic heterogeneity depending on the localization and selection of matched pairs. These findings are of specific importance in view of establishing prognostic markers.

Vascular Endothelial Growth Factor Expression Correlates with p53 Mutation and Angiogenesis in Squamous Cell Carcinoma of the Head and Neck

Vascular endothelial growth factor (VEGF) has potent angiogenic activity and has been identified in a wide variety of malignancies, including head and neck squamous cell carcinoma (HNSCC). The tumour-suppressor gene p53 has been thought to regulate VEGF. Cryostat sections of 33 head and neck squamous cell carcinomas (HNSCC) were immunostained for VEGF using a standard streptavidin-biotin complex procedure. To evaluate angiogenesis, microvascular density was counted by staining endothelial cells immunohistochemically using anti-vWF monoclonal antibody. The p53 gene status was analysed using a PCR-SSCP analysis and direct sequencing. VEGF positive staining was detected in 18 (55%) out of 33 tumours. VEGF immunoreactivity did not correlate with the main clinicopathological characteristics of the patients (localization, T-stage, N-status, histological grading). Statistical analysis gave a clear correlation between the tumour vascularity and the VEGF protein expression (p = 0.0036). VEGF negative tumours showed a lower mean number of microvessels per microscopic field (60.3 +/- 15.5) than VEGF positive tumours (79.6 +/- 22.9). P53 mutations were identified in 12 (36.4%) of 33 tumours. The association of p53 mutations and VEGF expression level was significant (0.027). The higher microvessel density in VEGF positive tumours supports the importance of VEGF for tumour angiogenesis in HNSCC. Our results support the hypothesis of a p53 regulation on the angiogenic process through a VEGF up-regulation.Vascular endothelial growth factor (VEGF) has potent angiogenic activity and has been identified in a wide variety of malignancies, including head and neck squamous cell carcinoma (HNSCC). The tumour-suppressor gene p53 has been thought to regulate VEGF. Cryostat sections of 33 head and neck squamous cell carcinomas (HNSCC) were immunostained for VEGF using a standard streptavidin-biotin complex procedure. To evaluate angiogenesis, microvascular density was counted by staining endothelial cells immunohistochemically using anti-vWF monoclonal antibody. The p53 gene status was analysed using a PCR-SSCP analysis and direct sequencing. VEGF positive staining was detected in 18 (55%) out of 33 tumours. VEGF immunoreactivity did not correlate with the main clinicopathological characteristics of the patients (localization, T-stage, N-status, histological grading). Statistical analysis gave a clear correlation between the tumour vascularity and the VEGF protein expression (p=0.0036). VEGF negative tumours showed a lower mean number of microvessels per microscopic field (60.3 15.5) than VEGF positive tumours (79.6 22.9). P53 mutations were identified in 12 (36.4%) of 33 tumours. The association of p53 mutations and VEGF expression level was significant (0.027). The higher microvessel density in VEGF positive tumours supports the importance of VEGF for tumour angiogenesis in HNSCC. Our results support the hypothesis of a p53 regulation on the angiogenic process through a VEGF up-regulation.

Current advances in the basic research and clinical management of juvenile-onset recurrent respiratory papillomatosis

Abstract Juvenile-onset recurrent respiratory papillomatosis is a relatively uncommon disease that presents clinically with symptoms ranging from hoarseness to severe dyspnea. Human papilloma viruses type 6 and 11 are important in the etiology of the papillomata and are most probably transmitted from mother to child during childbirth. Although spontaneous remission is frequent, a rare fatal course because of pulmonary spread or malignant transformation has occurred. CO2 laser evaporation of papillomas and adjuvant drug therapy using lymphoblastoid α-interferon are the most common treatment modalities at present. However, several other treatment modalities have been tried with varying success. Recent advances in basic research and different therapeutic approaches are reviewed.

Sinonasal Malignancy: What’s New?

Tumors of the nasal cavity are located at a complex anatomic site and show a huge histological diversity. Although dealing with a rare malignancy, the last decade has brought – besides new histological and clinical classifications – a variety of new insights into etiological agents, tumor biology and therapeutic concepts as well as valuable overviews of rare histological subtypes. This review tries to disentangle the different medical and scientific aspects of the most frequently encountered histological types of tumors in the nasal cavity and the paranasal sinuses. We concentrate on epidemiology, classification, etiology, cytogenetics and molecular genetics, outcome and prognosis as well as treatment modalities, as far as the past few years have brought considerable new insights. Our principal aim is to provide the clinician with important data from publications of the last decade.

Tumor-associated Antigens as Possible Targets for Immune Therapy in Head and Neck Cancer: Comparative mRNA Expression Analysis of RAGE and GAGE Genes

Specific immune therapy targeting residual areas of cancer cells may emerge as a powerful treatment strategy for head and neck squamous cell carcinoma (HNSCC). In order to define possible targets for immune therapy, we evaluated the frequency of two groups of tumor antigens - the RAGE and GAGE families - by means of reverse transcriptase polymerase chain reaction using primary HNSCCs ( n =28), mucosa specimens as normal controls ( n =10) and HNSCC cell lines ( n =6). By means of specific primer selection we could differentiate between RAGE-1, -2, -3 and-4, as well as between two groups of GAGE genes (GAGE-1,2,7 vs GAGE-3,4,5,6,8). While all mucosa tissues (from smokers and non-smokers) were negative for both antigen families, 24/28 investigated tumors were positive for up to 5 tumor antigens. Among the RAGE genes, RAGE-1-positive tumors were the most abundant (8/28), followed by RAGE-2 (7/28) and RAGE-4 (6/28). Differences in the locations of HNSCCs were reflected by different RAGE family members being expressed most frequently: larynx, RAGE-1; oropharynx, RAGE-2; and hypopharynx, RAGE-4. Primers against GAGE-1,2,7 and GAGE-3,4,5,6,8 revealed 6/27 and 16/27 positive tumors, respectively. This report suggests that RAGE genes and GAGE-3,4,5,6,8 may be promising candidates for specific immune therapy in HNSCC.

Co-expression of different angiogenic factors in external auditory canal cholesteatoma.

Objective Although external auditory canal cholesteatoma (EACC) was first described in 1850, its cause remains surprisingly unclear. Angiogenesis, the formation of new blood vessels, is essential to normal development and wound healing in adults. Abnormal regulation of angiogenesis has been implicated in the pathogenesis of several disorders. The aim of this study was to analyse angiogenesis regulator expression in EACC. Materials and Methods Cryostat sections of 13 investigated EACC tissue samples and normal control tissue were immunostained for angiogenic hepatocyte growth factor (HGF)/scatter factor (SF), its c-Met receptor and vascular endothelial growth factor (VEGF) using a standard streptavidin–biotin complex procedure. Staining against von Willebrand factor (vWF) served as an endothelial marker. Statistical analysis was performed semiquantitatively. Results The assayed angiogenic factors were all present in the EACC tissue, and partly overexpressed. vWF was detected in the apical layers of the matrix epithelium. Positive immunoreactivity for c-Met and VEGF was detectable in all layers of the EACC epithelium; however, adjacent tissue did not express c-Met and VEGF. HGF/SF was predominantly expressed in the adjacent perimatrix tissue and fibroblasts in particular were stained positive. Conclusions The presence of vWF in the apical part of the matrix depicted the attempt at angiogenesis in this part of the EACC. The detection of VEGF and c-Met in the epithelial part of the EACC implied that their origin may be epithelial, while HGF/SF may be secreted or stored in the adjacent mesenchymal EACC tissue. The angiogenic factors investigated seem to play an important role in establishing that EACC occurs by modulation of angiogenesis.