Erzsébet Lengyel

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.

A Review on Radiogenic Lhermitte's Sign *

Radiation myelopathy is a rare, but extremely serious side-effect of radiotherapy. Recovery from radiation-induced motor sequelae is rare, whereas, the regeneration of sensory losses is relatively frequent. Among the sensory radiogenic injuries of the spinal cord, Lhermitte’s sign (LS) is most frequent. This review describes the clinical picture and diagnostic imaging signs of radiogenic LS. There have been only a few studies on large patient groups with radiogenic LS, demonstrating a rate of occurrence of 3.6–13%, relating mainly to mantle irradiation or the radiotherapy of head and neck tumors. These cases typically manifest themselves 3 months following radiotherapy and gradually disappear within 6 months. Only 3 LS cases have been described in the English literature with extraordinarily severe symptoms lasting for more than 1 year. MRI, a sensitive tool in the detection of demyelination, failed to reveal any pathological sign accompanying radiogenic LS. However, positron emission tomography demonstrated increased [18F]fluorodeoxyglucose accumulation and [15O]butanol perfusion, but a negligible [11C]methionine uptake in the irradiated spinal cord segments in patients with long-standing LS. These imaging data are suggestive of a close direct relationship between the regional perfusion and metabolism of the spinal cord, very much like the situation in the brain. We postulate that an altered, energy-demanding conduction along the demyelinated axons of patients with chronic radiogenic LS may explain the increased metabolism and perfusion.

Increased Metabolic Activity in the Spinal Cord of Patients with Long-Standing Lhermitte’s Sign

Purpose:To investigate the pathophysiology of the radiation-induced, chronic Lhermitte’s sign (LS) on the basis of long-standing case histories with partial functional recovery.Patients and Methods:As radiotherapy in two nasopharyngeal cancer patients, a biologically effective dose (BED) of 103.8 Gy2 (case 1) and 94.8 Gy2 (case 2) was delivered to the cervical spinal cord. Neurologic signs relating to the irradiated spinal cord segments developed after 2 months (case 1) and 5 years (case 2), with radiation-induced damage equivalent to grade 3 (case 1) and grade 2 (case 2) toxicity (Common Toxicity Criteria, Version 2.0). The clinical status improved to grade 2 (case 1) and grade 1 (case 2). Positron emission tomography (PET) and fibroblast clonogen assay were applied 25 and 7 years postirradiation, respectively, to characterize this rare clinical picture.Results:PET demonstrated increased [18F]fluorodeoxyglucose (FDG) accumulation and [15O]butanol perfusion, but negligible [11C]methionine uptake in the irradiated spinal cord segments in both patients. In clonogenic assays, fibroblasts from case 1 displayed much higher radiation sensitivity than in healthy controls, while in case 2 the fibroblasts sensitivity was normal.Conclusions:These data suggests a close direct relationship between regional perfusion and metabolism of the spinal cord, similarly as in the brain. The postirradiation recovery may be related to energy-demanding conduction, explaining the increased metabolism and perfusion. The increased radiosensitivity and higher spinal cord BED may have contributed to the more severe sequelae in case 1.Ziel:Untersuchung der Pathophysiologie des strahleninduzierten chronischen Lhermitte-Zeichens auf der Basis der Langzeitbeobachtung von zwei Patienten mit partieller funktioneller Erholung.Patienten und Methodik:Bei zwei Patienten mit Nasopharynxkarzinom wurde die Halswirbelsäule mit einer biologisch effektiven Dosis (BED) von 103,8 Gy2 (Patient 1) bzw. 94,8 Gy2 (Patient 2) bestrahlt. Neurologische Symptome, die auf die bestrahlten Segmente des Zervikalmarks zurückzuführen waren, traten nach 2 Monaten (Patient 1) bzw. nach 5 Jahren (Patient 2) auf, wobei die strahleninduzierte Schädigung einer Grad-3- (Patient 1) bzw. Grad-2-Toxizität (Patient 2) entsprach (Common Toxicity Criteria, Version 2.0). Der klinische Status ging auf Grad 2 (Patient 1) bzw. Grad 1 (Patient 2) zurück. Positronenemissionstomographie (PET) und der Fibroblastenklonogenitätsassay wurden 25 bzw. 7 Jahre nach der Strahlentherapie eingesetzt, um dieses seltene Krankheitsbild zu charakterisieren.Ergebnisse:Im PET zeigten sich bei beiden Patienten eine erhöhte [18F-]Fluorodesoxyglucose-(FDG-)Aufnahme und [15O-] Butanol-Perfusion, jedoch eine vernachlässigbar geringe [11C-]Methionin-Aufnahme in den bestrahlten Segmenten. In den Klonogenitätsassays hatten die Fibroblasten des Patienten 1 eine höhere Strahlungsempfindlichkeit als bei gesunden Kontrollen, während die Fibroblastensensitivität bei Patient 2 normal war.Schlussfolgerungen:Diese Befunde sprechen für eine—ähnlich wie im Gehirn—enge direkte Beziehung zwischen regionaler Perfusion und Metabolismus des Rückenmarks. Die Erholung nach der Strahlentherapie dürfte mit Energie verbrauchenden Prozessen einhergehen, was die Steigerung von Metabolismus und Perfusion erklärt. Die erhöhte Strahlenempfindlichkeit und die höhere BED am Rückenmark können zu den gravierenderen Folgeerscheinungen bei Patient 1 beigetragen haben.

Reirradiation of locally recurrent nasopharyngeal carcinoma

Purpose: To study the efficacy of reirradiation as salvage treatment in patients with locally recurrent nasopharyngeal carcinoma. Patients and Methods: Between 1993 and 2000, 20 consecutive patients (twelve males and eight females) with nasopharyngeal cancer, previously irradiated in different Hungarian institutions, were reirradiated for biopsy-proven locally recurrent tumor. Histologically, 85% of the patients had WHO type III, 5% type II, and 10% type I disease. Stages I–IV (AJCC 1997 staging system) were assigned to five (25%), seven (35%), five (25%), and three (15%) patients, respectively; none of them had distant metastases, and only eight (40%) displayed regional dissemination. The median time period between termination of primary treatment and local recurrence was 30 (range, 10–204) months.Brachytherapy was the method most frequently used: in ten cases alone (especially for rT1 tumors), and in eight cases in combination with external beam therapy. Two patients with locally advanced disease underwent external beam therapy only. The median dose in the event of brachytherapy alone was 20 Gy (4 × 5 Gy or 5 × 4 Gy, range, 16–36 Gy), and the dose range for exclusive external irradiation was 30–40 Gy. In cases of combined irradiation, a median 20-Gy brachytherapy (range, 16–40 Gy) was associated with 30–40 Gy of external irradiation. Radiotherapy was supplemented by neck dissection (six patients), nasopharyngectomy (one patient), or chemotherapy (eleven patients). Results: 16 patients were reirradiated once, three twice, and one patient three times, with a median equivalent dose for tumor effect of 36 Gy (mean, 44 Gy; range, 19–117 Gy; the estimated α/β-ratio was 10 Gy). The median equivalent dose of reirradiation for late effect on normal tissue (with an estimated 70% delivery of the tumor dose) amounted to 30 Gy (mean, 37 Gy; range, 13–101 Gy, estimated α/β-ratio 3 Gy). After a median follow-up of 37 (range, 12–72) months, the overall survival was 60% (12/20). Seven of the twelve surviving patients are currently tumor-free. After primary irradiation, xerostomy occurred in all patients as an unavoidable side effect of treatment. Following reirradiation, a severe (grade 3 or higher) late toxicity (CTC criteria, version 2) has been observed in two tumor-free patients (10%) so far (necrosis of soft palate and paresis of glossopharyngeal nerve). Conclusion: Retreatment of nasopharyngeal carcinoma with radiotherapy (preferably a combined modality), can result in longterm local control and survival in a substantial proportion of patients, at the price of an acceptable morbidity.Ziel: Untersuchung der Effektivität einer Wiederbestrahlung als Palliativbehandlung bei Patienten mit lokal rezidivierendem nasopharyngealem Karzinom. Patienten und Methodik: Im Zeitraum von 1999 bis 2000 wurden 20 konsekutive Patienten (zwölf Männer und acht Frauen) mit nasopharyngealem Karzinom, die sich bereits früher in verschiedenen ungarischen Instituten einer Strahlentherapie unterzogen hatten, wegen eines bioptisch nachgewiesenen Rezidivtumors erneut bestrahlt. Histologisch gehörten 85% der Patienten dem WHO-Typ III, 5% dem Typ II und 10% dem Typ I an. Den Stadien I–IV (AJCC-Stagingsystem 1997) wurden fünf (25%), sieben (35%), fünf (25%) bzw. drei (15%) Patienten zugeordnet. Keiner der Patienten hatte Fernmetastasen, und nur acht (40%) zeigten eine regionale Disseminierung. Die mediane Zeitspanne zwischen Abschluss der primären Therapie und Auftreten des Lokalrezidivs betrug 30 (10–204) Monate.Die Brachytherapie wurde am häufigsten eingesetzt: in zehn Fällen allein (speziell für rT1-Tumoren) und in acht Fallen kombiniert mit einer externen Strahlentherapie. Zwei Patienten mit lokaler Krankheitsausbreitung wurden nur einer externen Strahlentherapie unterzogen. Die mediane Dosis betrug bei alleiniger Brachytherapie 20 Gy (4 × 5 Gy oder 5 × 4 Gy; Bereich 16–36 Gy). Der Dosisbereich für eine ausschließlich externe Bestrahlung lag zwischen 30 und 40 Gy. Bei kombinierter Bestrahlung war eine mediane brachytherapeutische Dosis von 20 Gy (Bereich 16–40 Gy) mit einer externen Bestrahlungsdosis von 30–40 Gy verbunden. Die Strahlentherapie wurde durch eine Neck-Dissection (sechs Patienten), Nasopharyngektomie (ein Patient) oder Chemotherapie (elf Patienten) ergänzt. Ergebnisse: 16 Patienten wurden einmal, drei zweimal und einer dreimal mit einer medianen tumorwirksamen Äquivalentdosis von 36 Gy (im Mittel 44 Gy, Bereich 19–117 Gy; geschätztes α/β-Verhältnis 10 Gy) wiederbestrahlt. Die mediane Äquivalentdosis der Wiederbestrahlung für den Späteffekt auf normales Gewebe (mit einer geschätzten Aufnahmerate von 70% der Tumordosis) lag bei 30 Gy (im Mittel 37 Gy, Bereich 13–101 Gy, geschätztes α/β-Verhältnis 3 Gy). Nach einer medianen Nachbeobachtungsperiode von 37 Monaten (Bereich 12–72 Monate) betrug die Gesamtüberlebensrate 60% (12/20). Sechs der zwölf überlebenden Patienten sind derzeit tumorfrei. Nach primärer Bestrahlung trat bei allen Patienten als unvermeidbare Nebenwirkung der Behandlung eine Xerostomie auf. Nach Wiederbestrahlung wurde bei zwei tumorfreien Patienten (10%) eine schwere (Grad 3 oder höher) Spättoxizität (CTC-Kriterien, Version 2) beobachtet (Nekrose des weichen Gaumens und Parese des Nervus glossopharyngeus). Schlussfolgerung: Die wiederholte Behandlung des nasopharyngealen Karzinoms mittels Strahlentherapie (vorzugsweise als kombinierte Modalität) kann bei einem beträchtlichen Patientenanteil in einer langfristigen lokalen Kontrolle und Überlebenszeit bei akzeptabler Morbidität resultieren.

Markov model-based estimation of individual survival probability for medullary thyroid cancer patients

The relatively benign, but occasionally rapidly fatal clinical course of medullary thyroid cancer (MTC) has raised the need for individual survival probability estimation. A retrospective study on 91 MTC clinical case histories with a mean follow-up of 6 years indicated prevalences of local, regional and distant residual tumor on primary care completion of 23%, 54% and 54%, respectively. Local, regional and distant relapses during follow-up occurred in 8%, 23% and 26% of the patients, with a cause-specific death in 26% of the cases. Prognostic factors statistically significantly influencing the cause-specific survival were selected by uni- and multivariate analysis. A Markov method-based model was developed for the estimation of individual time-dependent local, regional and distant relapse-free and cause-specific survival probability functions, with parameters numerically determined via a maximum likelihood procedure. These parameters include relative risk factors related to prognosticators, a residual or recurrent local/regional/distant tumor, and combinations of these entities. In multivariate studies, the patient’s age and gender, the genetic basis of the disease, lymph node involvement, the existence of a general symptom (diarrhoea) at presentation, and the dosage of external irradiation proved to be prognosticators. The cause-specific survival function of the study population indicated mean 5, 10 and 15-year survival probabilities of 69%, 62% and 58%. Conclusion: Survival probabilities can be predicted for extrastudy cases provided that the same laws and principles govern the clinical course of these cases and those comprising the study. For individual survival probability estimation, a Pascal program (MEDUPRED) was written and is available on the home page of the National Institute of Oncology, Budapest (www.oncol.hu).