Éva Remenár

Malignant mucosal melanoma of the head and neck — a review

Mucosal melanomas comprise about 1% of all malignant melanomas and exhibit far more aggressive behaviour than that of skin melanomas: they are more inclined to metastatize into regional and distant sites or recur locally, regionally or in distant locations, resulting in a high rate of cause-specific death. Mucosal melanomas in the head and neck region account for half of all mucosal melanomas, occurring mainly in the upper respiratory tract, oral cavity and pharynx. They appear with equal gender distribution and with a peak incidence in the age range 60–80 years. In consequence of their hidden location, they are usually diagnosed in a locoregionally advanced clinical stage, with a rate of 5–48% of regional and 4–14% of distant dissemination. The typical therapeutic approach is surgery, postoperative irradiation and systemic therapy. Local control with either surgery or radiotherapy is frequently (60–70%) achieved, but the rates of local, regional and distant recurrences are high (50–90%, 20–60% and 30–70%, respectively). The reported 5-year actual survival rates are poor (17–48%), which is attributed mainly to a haematogenous dissemination. These characteristics demonstrate that identification of the precursor lesions and more effective local and systemic approaches are needed to improve the therapeutic results.

Progression of head and neck squamous cell cancer

Squamous cell cancer in the head and neck region (HNSC) is unique concerning its progression since it remains locoregional for long time and visceral metastases develop only in a later stage of the disease. Accordingly, molecular markers of the local invasion and the lymphatic dissemination both have critical importance. HNSC progression is associated with deregulated control of cell proliferation and apoptosis but it seems equally significant the disregulation of the proteolytic machineries. Here we outline the lymphatic metastatic cascade for HNSC to depict key molecular determinants as possible prognostic factors or therapeutic targets identifying immunological selection as a major feature. Unlike in local spreading, invasive potential of cancer cells seems to be less significant during lymphatic dissemination due to the anatomical properties of the lymphatic vessels and tissues. There is a general believe that HNSC is one disease however, data indicate that the anatomical localization of the tumor (the “soil”) such as oral, lingual, glottic or pharyngeal has a significant effect on the gene expression profile and corresponding biological behavior of HNSC. Furthermore, even the endocrine milieu of the host was proved to be influential in modulating the progression of HNSC. Gene expression profiling techniques combined with proteomics could help to define and select usefull genetic and biomarkers of progression of HNSC, some of them could well be potential novel therapeutic target.

Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma Modulates Intratumoral CD4/CD8 Ratio and Tumor Microenvironment: A Multicenter Phase II Clinical Trial

PURPOSE To investigate the clinicopathologic effects of local neoadjuvant Leukocyte Interleukin Injection (LI) regimen in oral squamous cell carcinoma (OSCC) patients. Treatment regimen included LI 800 IU/d as interleukin-2 (IL-2), administered half peritumorally and half perilymphatically five times per week for 3 weeks; low-dose cyclophosphamide; indomethacin; zinc; and multivitamins. PATIENTS AND METHODS Thirty-nine patients diagnosed with T2-3N0-2M0 OSCC participated in the pathology portion of this phase II multicenter study (19 LI-treated patients and 20 historical controls). Clinical responses were determined by imaging. Paraffin-embedded tumor samples were obtained at surgery for all patients. Surgery for the LI-treated group was performed between days 14 and 54 after the end of treatment. Histologic evaluation, pathologic staging, necrosis, and American Joint Committee on Cancer grading were performed from hematoxylin and eosin sections. Immunohistochemistry and morphometry determined cellular infiltrate. RESULTS Two pathologically complete, two major (> 50%), and four minor responses (> 30% but < 50%) resulted from LI treatment (overall response rate, 42%). Histopathology showed that the intratumoral CD4+:CD8+ ratio was low (< 1) in patients not treated with LI (controls). An increase in tumor-infiltrating CD4+ and a decrease of CD8+ T cells was observed in LI-treated patients, leading to a significantly (P < .05) higher intratumoral CD4+:CD8+ ratio (> 2.5). This was paralleled by dendritic cell transition from tumor surface toward stromal interface (P < .05), with macrophage decrease and neutrophil accumulation, multifocal microscopic necrosis, and significant (P < .05) increase in tumor stroma of LI-treated patients compared with controls. CONCLUSION LI-treated OSCC patients were characterized by a markedly altered composition of tumor-infiltrating mononuclear cells, increased CD4+:CD8+ ratio, and increased tumor stroma to epithelial ratio, all of which were distinct from controls.

Interstitial high-dose-rate brachytherapy in the treatment of base of tongue carcinoma

Background and Purpose:To date none of the studies examined the feasibility and efficacy of interstitial high-dose-rate (HDR) brachytherapy in the treatment of carcinoma of the tongue base. Therefore the aim of this study was to contribute to this issue.Patients and Methods:Between 1992 and 2000 37 patients (mean age 55 years) with T1–4 and N0–3 carcinoma of the base of tongue were presented. Neck dissection was carried out in twelve cases (32%). 30 patients with advanced stage received brachytherapy boost after 50–66.5 Gy (mean, 60 Gy) locoregional external beam irradiation (EBI) and 7 patients with early stage (T1–2, N0) were managed locally with wide tumor excision and sole brachytherapy. 4 of them underwent neck dissection and the others were subjected to 50 Gy regional EBI. The mean dose of boost and sole brachytherapy was 18 Gy and 28 Gy, respectively.Results:The median follow-up time for surviving patients was 51 months. The 7 sole brachytherapy patients are living with no evidence of disease. For patients treated with EBI and brachytherapy boost, the 5-year actuarial rate of local, locoregional recurrence-free and overall survival was 60%, 52% and 46%, respectively. For all patients in univariate analysis larger tumor size (T4 vs. T1–3) was significant negative predictor of local (RR: 7.23) and locoregional control (RR: 3.87), but nodal involvement was not. Delayed soft tissue ulceration and osteoradionecrosis occurred in 4 (13%) EBI and brachytherapy treated patients. None of the sole brachytherapy patients experienced severe late radiation toxicity.Conclusion:EBI combined with interstitial HDR brachytherapy boost result in acceptable local tumor control with low incidence of late side effects in patients with advanced disease. Fractionated sole HDR brachytherapy following tumor excision is a feasible treatment option for patients with early stage cancer and gives excellent local results.Hintergrund und Ziel:Zurzeit liegt keine internationale Studie vor, die die Anwendbarkeit und Wirksamkeit der interstitiellen High-Dose-Rate-(HDR-)Brachytherapie in der Behandlung des Zungengrundkarzinoms untersucht. Ziel dieser Arbeit ist es, unser Petientenkollektiv retrospektiv zu analysieren und unsere Therapiestrategien vorzustellen.Patienten und Methode:Zwischen 1992 und 2000 wurden 37 Patienten (Durchschnittsalter: 55 Jahre) mit Zungengrundkarzinomen im Stadium T1–4 N0–3 behandelt. In zwölf Fällen (32%) wurde eine Neck Dissection durchgeführt. 30 Patienten im fortgeschrittenen Tumorstadium erhielten nach lokoregionaler externer Bestrahlung (EBI) mit 50–66.5 Gy (durchschnittliche Dosis 60 Gy) anschließend einen Brachytherapie-Boost. Bei 7 Patienten im frühen Tumorstadium (T1–2, N0) wurde nach weiter Tumorexzision eine alleinige Brachytherapie durchgeführt. Im Anschluss daran erfolgte in vier Fällen eine Neck Dissection; die übrigen erhielten eine lokoregionale EBI bis 50 Gy. Die durchschnittliche Boostdosis bzw. alleinige Brachytherapiedosis waren 18 Gy und 28 Gy.Ergebnisse:Die mediane Nachbeobachtungszeit betrug 51 Monate. 7 Patienten, die mit alleiniger Brachytherapie behandelt wurden, leben seither tumorfrei. Die Rate bezüglich der 5-jährigen lokalen, lokoregionalen Rezidivfreiheit und der Gesamtüberlebenszeit bei Patienten, die mit EBI und Brachytherapie-Boost behandelt wurden, betrug 60%, 52% bzw. 46%. Eine univariate Analyse konnte zeigen, dass das Tumorvolumen (T4 vs. T1–3) für alle Patienten ein signifikant negativer Prädiktor bezüglich der lokalen (RR: 7,23) und lokoregionalen Tumorkontrolle (RR: 3,87) war. Dies galt nicht für die Lymphknoteninfiltration. Als Spätfolgen traten bei 4 Patienten (13%), die mit EBI und Brachytherapie behandelt wurden, ein Weichteilulkus und eine Osteoradionekrose auf. Bei Patienten, die mit einer alleinigen Brachytherapie behandelt wurden, traten keine Spätnebenwirkungen auf.Schlussfolgerung:EBI gefolgt von interstitieller HDR-Brachytherapie führt zu einer annehmbaren lokalen Tumorkontrolle bei Patienten mit fortgeschrittenen Karzinomen, wobei das Risiko chronischer Spätfolgen gering ist. Karzinome im Frühstadium profitieren von der lokalen Tumorexzision gefolgt von fraktionierter HDR-Brachytherapie. Es werden damit ausgezeichnete lokale Ergebnisse erreicht.

Radiotherapy and concurrent low-dose paclitaxel in locally advanced head and neck cancer

In our prospective study we examined the use of low-dose paclitaxel concurrently with radiation for patients with locally advanced head and neck cancer, who were not eligible for concurrent chemoradiation due to their poor general condition. Twenty-six patients were treated with external beam radiotherapy and received concomitantly 2 mg/m(2) paclitaxel three times a week. Beside an acceptable efficacy (RR: 65%, 2-year overall survival 46%) the treatment was well tolerated and resulted in a favorable toxicity profile. This regimen is resource effective and allowed successive therapy if it was necessary and therefore may serve as an alternative for patients in poor condition with locally advanced head and neck cancer.

Antiangiogenic effects of radiotherapy but not initial microvessel density predict survival in inoperable oropharyngeal squamous cell carcinoma

Purpose:To evaluate the predictive value of intratumoral microvessel density (MVD) in patients with locally advanced, primarily inoperable oropharyngeal cancer (OPCC) treated with irradiation alone.Patients and Methods:Tumor samples of 35 patients with OPCC subjected to radiotherapy were taken before and after 20 Gy irradiation. Histological grade, mitotic activity index and MVD of OPCC were determined. Correlations with response and survival were analyzed.Results:Stage and posttreatment MVD decrease showed significant correlation with objective response. Postirradiation MVD decrease correlated significantly with response to irradiation and overall survival, and a trend could be seen for progression-free survival.Conclusion:This study has shown that the change in MVD after irradiation can be an indicator of the success of radiotherapy in locally advanced OPCC, and may serve as a predictive factor thus helping to select patients who could benefit from more aggressive treatment.Ziel:Untersuchung des prädiktiven Werts der Tumorkapillardichte bei Patienten mit alleiniger Radiotherapie lokal fortgeschrittener, primär inoperabler Oropharynxkarzinome (OPCC).Patienten und Methodik:Bei 35 Patienten mit Oropharynxkarzinomen wurden vor und nach Erreichen einer Gesamtreferenzdosis von 20,0 Gy Gewebeproben entnommen. Histologischer Grad, mitotischer Index und Kapillardichte wurden bestimmt. Zum Nachweis eines möglichen Zusammenhangs mit der Ansprech- und Überlebensrate wurde eine statistische Analyse durchgeführt.Ergebnisse:Tumorstadium und niedrige Kapillardichte nach Bestrahlung hatten einen signifikanten Einfluss auf das Tumoransprechen. Das Tumoransprechen und eine niedrige therapieinduzierte Kapillardichte erwiesen sich als prognostisch günstig für das Gesamtüberleben und das progressionfreie Überleben.Schlussfolgerung:Das Ausmaß der antiangiogenen Wirkung einer Bestrahlung kann bei lokal fortgeschrittenem Oropharynxkarzinom als Indikator für den Therapieerfolg dienen. Als prädiktiver Faktor könnte es sich auch für die Selektion von Patienten eignen, die vor einer aggressiven Behandlung profitieren.

The Morphological Basis for Development of Reinke's Oedema

Normal human vocal cords and surgically removed Reinkes oedema were studied by light and electron microscopy. The Reinkes space between the lamina propria and vocal ligament was filled with loose connective tissue sheets, which seemed to be an organic part of the vocal ligament. The structure suggested the possibility of the lamellae moving on each other. This could be important for the vibratory function of vocal cords. Inside the lamellae, masses of inmature young elastic fibres were found. Reinkes oedema develops in the superficial elastic sheets. Therefore in the case of surgical intervention the specially structured rubbery elastic vocal cord mucosa must be removed, which is essential to perfect vibratory function.

Fibula-szabadlebennyel nyert tapasztalataink

Oral cancer incidence in Hungary is strikingly high, even by international standards. In most cases the tumours are to be treated in advanced stage. Hence it follows that we are often forced to remove a part of the mandible, too. We usually use a fibula free flap to reconstruct the bone deficiency. In this paper we report on our clinical experience with fibula free flap.

Increase of hypophyseal hormone levels in male head and neck cancer patients

Head and neck squamous cell carcinoma (HNSCC) develops in at least 80% of cases in men with a history of smoking and heavy alcohol consumption, still it is only diagnosed in a small proportion of alcoholics. Endocrine milieu is an important factor in carcinogenesis and prognosis of several cancer types. The aim of our study was to investigate sex steroid and hypophyseal hormone status of male HNSCC patients in comparison to healthy volunteers and to patients with alcoholic liver disease, to determine possible hormonal alterations characteristic of cancer. Liver function (GGT level), and serum levels of gonadotropic hormones (FSH, LH, prolactin), sex steroids (estradiol, progesterone, testosterone) and sex hormone-binding globulin (SHBG) were compared in 130 male HNSCC patients, 54 patients with alcoholic liver disease but no known cancer, and 56 healthy controls. We found abnormal values of liver function in both HNSCC patients and alcoholics compared to healthy controls, suggesting the presence of alcoholic liver disease in the former group as well. On the other hand, a significant elevation in the level of DHEA, FSH and LH was observed in cancer patients exclusively. As a conclusion, abnormal alterations in sex steroid hormone levels can frequently be found in HNSCC patients, which may be caused in part by the alcoholic liver damage accompanying the disease. The significant increase in FSH and LH serum levels, observed only in the cancer patients, indicates that these hormones may play a role in the development and/or progression of HNSCC.

Citogenetikai és hormonális változások fej-nyaki laphámrákos betegekben: potenciális biomarkerek a funkciómegtartó onkológiai sebészet számára@@@Cytogenetic and hormonal changes in head and neck squamous cell cancer patients: potential biomarkers for functional approaches in surgical oncology

Squamous cell cancer of the head and neck (SCCHN) is the third most common cause of death from cancer among Hungarian males. This cancer is caused in most of the cases by chronic toxic effects of the environment, especially by tobacco smoking and regular alcohol consumption. SCCHNs similar for the first sight, might have different clinical course, mainly because of their different responses to anticancer therapies. In this study, potential biomarkers were examined that were thought to develop as biologic responses to the known environmental toxicities, therefore, their testing is supposed to help answer the most important questions of clinical oncology: understanding tumor development, early detection of cancer and individually tailored therapy planning based on the biological nature of a particular cancer. Elevated rate of spontaneous chromosome aberrations proved to be a reliable marker of the SCCHN phenotype. However, increased mutagen sensitivity by the bleomycin-test, unlike in the US or in Western Europe, was not suitable to detect the individual cancer risk in this country, because of the high mutagen sensitivity of more than half of the healthy Hungarian population examined. In the light of the high cancer incidence and mortality statistics of Hungary, the frequency of elevated mutagen sensitivity even among healthy people is a meaningful finding, and requires further clarification. Our studies on the hormonal status of male SCCHN patients revealed some pathological changes in the sex steroid and pituitary hormone serum levels, which most probably accompanied chronic alcoholic liver disease. The elevated prolactin and decreased total and free testosterone levels predicted poor prognosis of the disease. The importance of the potential relationship between hormones and SCCHN is underscored by our further finding of functioning estrogen and progesterone receptors in SCCHN tissue of our patients.