R. Knecht

Human epidermal growth factor receptor 2 (HER2) in salivary gland carcinomas

Background: HER2 is a target for antibody-based treatment of breast and gastric carcinoma which is highly successful in advanced disease as well as in the adjuvant setting. To determine the potential applicability of such therapies, salivary gland tumours were analysed for HER2 overexpression/amplification in this study. Methods: A tissue microarray (TMA) was constructed from 994 carcinomas and 205 adenomas of the salivary gland. Slides were analysed for HER2 overexpression and gene amplification using FDA approved reagents for immunohistochemistry (IHC; Hercep-Test; Dako) and fluorescence in situ hybridisation (FISH; PathVysion; Vysis-Abbott). Results: HER2 was found overexpressed in 39 of 915 (4.26%) and amplified in nine of 915 interpretable salivary gland carcinomas (0.98%). HER2 overexpression was mostly found in salivary duct carcinoma. All other entities were mainly HER2 negative. HER2 was overexpressed in 34 of 319 (10.65%) mucoepidermoid carcinomas, one of 170 (0.59%) acinic cell adenocarcinomas and three of 14 (21.43%) salivary duct carcinomas. HER2 amplification was seen in three of 294 (1.01%) mucoepidermoid carcinomas, three of 14 (21.43%) salivary duct carcinomas, one of 81 (1.23%) adenocarcinomas (NOS), one of 12 (8.33%) cystadenocarcinomas and one of 19 (2.08%) myoepithelial carcinomas. HER2 amplification was found in seven of 39 immunohistochemically HER2 positive (2+ and 3+) tumours (17.95%) but in only two of 849 (0.24%) IHC negative tumours (p < 0.0001). No amplification/overexpression was found in adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous low grade carcinoma, basal cell carcinoma, myoepithelial carcinoma, cystadenocarcinoma and oncocytic carcinoma. Conclusion: HER2 overexpression caused by gene amplification was observed in about 20% of patients with salivary duct cancers but was rare in salivary adenomas and other carcinomas. Therefore, anti-HER2 therapy may represent a therapeutic option only in a small subgroup of salivary gland tumours.

The endoscopic approach to the Neck: A review of the literature, and overview of the various techniques

BackgroundThe endoscopic surgical approach to the neck has reached the head and neck surgeons’ view with a certain delay, compared to other fields of endoscopic procedures. This may be attributed to the tight work space and plenty of vital structures in the operating field. Since study groups described first attempts with endoscopic or video assisted removals of thyroid glands in the late nineties, selective neck dissections on animal models or cadaveric dissections were performed in 2003.MethodThe review consists of a Medline Search regarding the terms of endoscopic, video- assisted neck dissections, excision of neck lesions, thyroidectomy and submandibular resection and minimal access surgery. The three main procedures (selective neck dissection, submandibular resection and thyroidectomy) are described and reviewed in the following test.ResultsVarious techniques have been performed successfully and led to good clinical results. The studies described in literature other than for thyroidectomy often do not exceed the level of small series or case-reports.ConclusionWith a good proof of indication gasless lifting techniques, video assisted endoscopical techniques and subcutaneous approaches with gas filling procedures are feasible in neck surgery. All methods depending on the surgeons’ experience describe no significantly extended operation times, a better and faster wound-healing and an optimized cosmetic outcome, compared to open approaches. Surgeons should always be aware of the limitations of the minimal invasive techniques regarding the complications or modifications during neck dissection/thyroidectomy.

New treatment strategies for HPV-positive head and neck cancer

Epidemiological studies show an increasing incidence of human papilloma virus-associated oropharyngeal cancer. HPV-positive head and neck squamous cell carcinoma (HNSCC) is recognized as a special subgroup of HNSCC. Because HPV-positive patients are often younger and have an outstanding prognosis, long-term toxicities of therapy have become an important issue. Current clinical trials focus on a reduction of treatment-related toxicity and the development of HPV-specific therapies. New treatment strategies include a dose reduction of radiotherapy, the use of cetuximab instead of cisplatin for chemoradiation and transoral robotic surgery (TORS). Increasing comprehension of the molecular background of HPV-associated HNSCC has also lead to more specific treatment attempts including immunotherapeutic strategies. Whereas recently published data shed light on immune mechanisms resulting in a tolerogenic niche for HPV and HPV-associated HNSCC, other studies focus on specific vaccination of HPV-positive HNSCC. This study will summarize current therapy approaches and illustrate ongoing clinical trials in the field of HPV-positive HNSCC.

11q21 rearrangement is a frequent and highly specific genetic alteration in mucoepidermoid carcinoma.

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. Translocation t(11;19)(q21;p13) involving the MECT1 and MAML2 genes has been suggested as a diagnostic marker in these tumors. To determine the specificity of 11q21 locus rearrangements for MEC, fluorescence in situ hybridization analysis with specific MEC-I Dual Color Break Apart Probe was performed on a tissue microarray containing samples from almost 1200 salivary gland adenomas and carcinomas. Rearrangements of 11q21 were observed in 40% of 217 MECs. The frequency of rearrangements decreased with tumor grade and was found in 53% of G1, 43% of G2, and 31% of G3 tumors (P=0.015). There were no 11q21 rearrangements found in other salivary gland carcinomas including 142 adenoid cystic carcinomas, 104 acinic cell adenocarcinomas, 76 adenocarcinoma not otherwise specified, 38 epithelial-myoepithelial carcinomas, 15 polymorphous low-grade adenocarcinomas, 18 basal cell adenocarcinomas, 19 myoepithelial carcinomas, 12 papillary cystadenocarcinomas, 6 salivary duct carcinomas, and 10 oncocytic carcinomas. Furthermore, all analyzed salivary gland adenomas, including 39 cases of Warthin tumor and control samples, either from the salivary gland or from other organs were negative for 11q21 rearrangements. It is concluded that MECT1-MAML2 gene fusion is a highly specific genetic alteration in MEC with predominance in low-grade and intermediate-grade tumors.

Functional outcomes, feasibility, and safety of resection of transoral robotic surgery: Single-institution series of 35 consecutive cases of transoral robotic surgery for oropharyngeal squamous cell carcinoma

This is a single‐institution prospective study in a tertiary care center to evaluate feasibility, completeness of resection, and functional outcomes for oropharyngeal squamous cell carcinoma (SCC) treated primarily with transoral robotic‐assisted resection.

Geographical and anatomical influences on human papillomavirus prevalence diversity in head and neck squamous cell carcinoma in Germany

The increased knowledge regarding HPV-infections in head and neck squamous cell carcinoma (HNSCC) has unexpectedly contributed to several uncertainties related to i) prevalence diversities depending on tumour site and geographical origin of the patients, ii) proportion of HPV-driven tumours among HPV-DNA-positive cases, and iii) identification of patients with HPV-attributed survival benefit. To investigate this heterogeneity, we analysed 307 HNSCC cases (tonsillar, n=135; non-tonsillar, n=172) from eight health care centers mostly from Northern Germany and determined HPV-DNA/mRNA and p16INK4A-status and combined results with the patient outcome. Overall HPV-DNA prevalence rate was 23.5% (72/307); attributed to: 43.7% (59/135) and 7.6% (13/172) tonsillar and non-tonsillar cases, respectively. Among these, 96.6% tonsillar and 38.5% non-tonsillar SCC were HPV-mRNA-positive. Although the study cohort was composed of patients from regions of rather close proximity, prevalence rates showed diversities of up to 40% in HNSCC subsite analysis with the lowest prevalence for tonsillar SCC in metropolitan areas (22.2%) vs. 50.9% in rural areas. Survival analysis identified p16INK4A alone as strongest predictor, followed by HPV-DNA-status alone or in combination with p16INK4A. This survival benefit was shown for tonsillar and non-tonsillar cases. Smoking significantly correlated with HPV-status, however, it does not influence survival when stratified for HPV. In conclusion, the data emphasize the urge for further data on HPV-infection in HNSCC to, e.g. clarify to what extent survival benefits of p16INK4A-positive patients are truly attributed to HPV-infections.

Circulating tumor cells in head and neck cancer: clinical impact in diagnosis and follow-up

Metastasis and the associated loss of function of vital organs in the course of the disease is one of the main causes of death in head and neck cancer patients. An earlier and more reliable determination of metastasis and recurrence than currently obtained by common imaging methods could improve therapy and therefore the prognosis of head and neck cancer patients. The detection of tumor cells, which circulate in the blood of cancer patients, known as circulating tumor cells and those that can be found in the bone marrow, called disseminated tumor cells (DTC) provides a diagnostic source especially for those patients at high risk of locoregional recurrence or distant failure. Circulating tumor cells (CTC) have been identified as a prognostic factor in different solid tumors. In head and neck squamous cell carcinoma, there are data for a similar prognostic relevance. The methods of detection of CTC/DTC, the role in diagnosis and follow-up in head and neck cancer are summarized in this review. Furthermore, the future technical and clinical challenges to be addressed to establish CTC/DTC in clinical routine are being critically discussed.

Epidermal growth factor receptor (EGFR) in salivary gland carcinomas: Potentials as therapeutic target

AIMS Epidermal growth factor (EGFR) is involved in angiogenesis, cell differentiation, proliferation and progression of many cancers and is an important therapy target in lung and colorectal cancer. To determine the potential applicability of EGFR targeted therapies, EGFR status of over 800 salivary gland tumors of different entities were analyzed on DNA and protein level by FISH and IHC. MATERIALS AND METHODS A tissue microarray was constructed from 721 carcinomas and 205 adenomas of the salivary gland. EGFR expression and EGFR gene copy number was assessed by means of immunohistochemistry and fluorescence in situ hybridization (FISH). EGFR mutation analysis of exon 19 and 21 was performed in a subset of 107 carcinomas. RESULTS Positive immunohistochemical staining (definition?) for EGFR was shown in 324 of 663 (48.9%) salivary gland carcinomas. The frequency was dependent on the tumor entity and ranged from 17.9% (30 of 168 cases) positive immunostaining in acinic cell adenocarcinomas to 85.7% (42 of 49 cases) in Warthin tumors. No EGFR amplification was found by FISH. EGFR mutation analysis of Exon 19 and 21 in 107 salivary gland carcinomas revealed mutations in two acinic cell adenocarcinomas. CONCLUSION EGFR protein expression is common in salivary gland tumors but is not associated with gene amplification. Activating mutations of EGFR are rare. Nonetheless, selected cases of patients with salivary gland carcinomas might potentially benefit of anti-EGFR therapy.

Current treatment options for recurrent/metastatic head and neck cancer: a post-ASCO 2011 update and review of last year's literature

The majority of patients with a squamous cell carcinoma of the head and neck present with locally advanced tumors. The first-line treatment of locally advanced tumor stages consists of a combined modality management. Despite these aggressive protocols, many patients develop locoregional recurrences or metastasis and place particularly high demands on the interdisciplinary treatment team. Treatment with a curative intent must be differentiated from a palliative one. In addition to prior treatment, resectability, age and performance status, patient wishes must be taken into consideration in treatment planning, especially considering that most therapies offer little to no overall survival benefit. Salvage surgery, chemo- and target therapies, and reirradiation are head and neck surgeon’s and radiooncologist’s weapons in the fight against these strong opponents. This review focuses on publications and meeting news from last year and reviews the current status of the clinical application of each treatment modality in recurrent or metastatic head and neck cancer.

Human papilloma virus in locally advanced stage III/IV squamous cell cancer of the oropharynx and impact on choice of therapy.

Oropharyngeal cancers (OPCs) are now believed to arise from two distinct pathways: one influenced by alcohol and tobacco use and the other a result of genomic instability induced by the human papilloma virus (HPV). The incidence of HPV-associated OPC is increasing, particularly among younger males. Case series and clinical trials suggest that patients with HPV-positive OPC have better clinical outcomes than those with HPV-negative tumors. We evaluated efficacy data in published articles and meeting abstracts from clinical studies comparing response rates and survival outcomes in patients with HPV-positive and -negative locally advanced OPC. Eight clinical studies were identified: half were prospective analyses of outcome according to HPV status; the remaining four reports were retrospective analyses. The majority of these analyses showed that patients with HPV-positive tumors had significantly better responses to treatment than those with HPV-negative tumors. In the two studies in which the effect of treatment was also evaluated, patients with HPV-positive tumors did not benefit significantly from intensive therapy, unlike those with HPV-negative tumors. HPV-positive tumor status is an important prognostic factor associated with a favorable outcome in patients with locally advanced OPC. The HPV status of patients with locally advanced OPC should be established before treatment commences. Surgery is well accepted in the treatment of OPC, but the place of chemoradiotherapy has yet to be confirmed. Prospective, well-controlled clinical studies are required to establish whether chemoradiotherapy provides an acceptable risk-benefit balance versus high-quality radiotherapy alone in patients with HPV-positive OPC, in whom the goal is to maximize progression-free and overall survival, while preserving function and maintaining quality of life.