Familial clustering of nasopharyngeal carcinoma in a non-endemic geographical region. Report of two Hungarian cases and a review of the literature.

The aim of this study was to investigate the familial clustering of nasopharyngeal carcinoma (NPC) in a non-endemic geographical region on the basis of two case reports and a review of the literature. Following an upper respiratory infection, NPC (WHO type III) was detected in a 57-year-old female (Case 1) who presented with nasal symptoms and a year later in her 36-year-old son (Case 2) who presented with enlarged lymph nodes. After a full diagnostic work-up, cT2a cN0 cM0 (stage IIA; Case 1) and cT2a cN2 cM0 (stage III; Case 2) disease were identified, and telecobalt irradiation was administered to both patients. The mother achieved complete remission and has been disease-free during a 14-year follow-up period. After initial complete remission, the son experienced regional (cervical) and base of the skull relapses within 2 years, which were treated unsuccessfully by means of radical neck dissection, a second course of radiotherapy and chemotherapy. Epstein-Barr virus (EBV) was detected in pathology sections from both patients. The authors review 20 additional well-documented cases of familial clustering of NPC in non-endemic geographical regions from the English language literature. This clinical entity typically has WHO type III histology; it may occur following an upper respiratory tract infection, and EBV-related serological titers were elevated in all 20 investigated cases. No consequent promoting factors were identified. The present two cases and the review of the literature strongly suggest that familial clustering of NPC in non-endemic geographical areas may be related to EBV infections. The difference in outcome of our two cases may be explained by the fact that the disease in Case 2 was diagnosed 1 year later than that in Case 1 and hence at a more advanced stage.

PET identifies transitional metabolic change in the spinal cord following a subthreshold dose of irradiation.

Positron emission tomographic (PET) investigations were performed to obtain in vivo information on symptomless radiation-induced pathological changes in the human spinal cord. PET investigations were carried out prior to radiotherapy and during the regular follow-up in an early hypopharyngeal cancer patient (the spinal cord was irradiated with a biologically effective dose of 80 Gy2), with [18F]fluorodeoxyglucose (FDG), [11C]methionine and [15O]butanol as tracers; radiosensitivity and electroneuronographic (ENG) studies were also performed. A very low background FDG accumulation (mean standardized uptake values, i.e. SUV: 0.84) was observed in the spinal cord before the initiation of radiotherapy. An increased FDG uptake was measured 2 months after the completion of radiotherapy (mean SUV: 1.69), followed by a fall-off, as measured 7 months later (mean SUV: 1.21). By 44 months after completion of irradiation, the FDG accumulation in the irradiated segments of the spinal cord had decreased to a level very close to the initial value (mean SUV: 1.11). The simultaneous [15O]butanol uptake results demonstrated a set of perfusion changes similar to those observed in connection with the FDG accumulation. The patient exhibited an extremely low [11C]methionine uptake within the irradiated and the nonirradiated spinal cord during the clinical course. She has not had any neurological symptoms, and the results of central ENG measurements before radiotherapy and 2 months following its completion proved normal. Radiobiological investigations did not reveal unequivocal signs of an increased radiosensitivity. A transitory increased spinal cord FDG uptake following radiotherapy may be related to the posttherapeutic mild inflammatory and regenerative processes. The normal [11C]methionine accumulation observed is strong evidence against intensive cell proliferation. The high degree of normalization of the temporarily increased FDG uptake of the irradiated spinal cord segments by 44 months is in good agreement with the results of monkey studies, which demonstrated a nearly complete recovery from radiation-induced spinal cord injury.

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 Gy(2) (case 1) and 94.8 Gy(2) (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 [(18)F]fluorodeoxyglucose (FDG) accumulation and [(15)O]butanol perfusion, but negligible [(11)C]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.

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.

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 x 5 Gy or 5 x 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 alpha/beta-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 alpha/beta-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.

Malignant mucosal melanoma of the head and neck.

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.

[Repeated radiotherapy in locally recurrent nasopharyngeal cancer]. / Az epipharynxrák lokális kiújulásának ismételt sugárkezelése.

PATIENTS AND METHODS: In the period between 1993 and 2000, 20 patients with nasopharyngael cancer were re-irradiated for locally recurrent carcinomas. The median duration between primary treatment and recurrence was 30 months. Brachytherapy was the method most frequently used in 10 cases alone, and in 8 cases in combination with external beam therapy. 2 patients underwent only external beam therapy. The external irradiation was performed with CT/MRI-based treatment planning. Brachytherapy involved a high dose rate afterloading method. The cumulative dose of re-irradiation was 20-60 Gy. RESULTS: After a median follow-up of 37 months the overall survival and the local control were 60% (12/20) and 58% (7/12), respectively. 7 of the 12 surviving patients are currently tumour-free. After primary irradiation xerostomy occurred in all patients as an unavoidable side-effect of the treatment. A severe (grade 3 or higher according to the Common Toxicity Criteria version 2.0) late-side effect has so far been observed in 2 cases (10%). Authors' results lie in the medial range of the data in the international literature, though the rate of radiogen side-effects in the patient group is low. Both results are assumed to be a consequence of the re-irradiation dose being lower than the value considered optimum in the recent literature. CONCLUSIONS: Re-irradiation of locally recurrent nasopharyngeal cancers is an efficient treatment modality, which should be used as a combination of external beam therapy and brachytherapy. The optimum cumulative dose is about 50-60 Gy. This dose results in a 5 years survival rate of about 40% with an acceptable (30%) risk. The results of re-irradiation may be improved, if PET is used to determine the extent of the surviving tumour tissue. This can help in the choice of the proper treatment modality.

[Cost-effective PET investigations in oncology]. / Költség-hatékony onkológiai PET-vizsgálatok.

The authors have reviewed the financial considerations of oncological FDG PET examinations by the guidelines of the Health Care Financing Administration (USA). By critical assessment of large number of clinical investigations,the cost-effectiveness of FDG PET scans has been confirmed in the following cases: differential diagnosis of solitary pulmonary nodule, diagnosis,staging and restaging of non-small cell lung cancer, colorectal cancer, malignant lymphomas, melanoma malignum, esophageal neoplasms and cancers of the head and neck. The role of this method in breast cancer is currently under intensive investigation. Due to the correct staging, PET examinations in these indications enable the clinicians to choose the optimal treatment ensuring the maximum probability of recovery and being cost-effective as unnecessary medical interventions become avoidable.

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

UNLABELLED: 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 dis-ease, 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).

[Cost-effective PET scans in oncology]. / Költséghatékony onkológiai PET-vizsgálatok.

The authors have reviewed the financial considerations of oncological FDG PET examinations by the guidelines of the Health Care Financing Administration (USA). By critical assessment of large number of clinical investigations, the cost-effectiveness of FDG PET scans has been confirmed in the following cases: differential diagnosis of solitary pulmonary nodule, diagnosis, staging and restaging of non-small cell lung cancer, colorectal cancer, malignant lymphomas, melanoma malignum, esophageal neoplasms and cancers of the head and neck. The role of this method in breast cancer is currently under intensive investigation. Due to the correct staging, PET examinations in these indications enable the clinicians to choose the optimal treatment ensuring the maximum probability of recovery and being cost-effective as unnecessary medical interventions become avoidable.

[PET scan and double-independent pathologic investigations effectively support the detection of occult primary tumors]. / A PET és a kettós, független patológiai leletezés hatékonyan támogatják a rejtett primer tumorok keresését.

Following the failure of conventional diagnostic procedures, whole-body FDG-PET investigations were carried out in 42 metastatic cancer patients to localize occult primary carcinomas. During the clinical follow-up, the presence of malignant tumor was ruled out in 3 cases, and 2 patients originally believed to have carcinoma were confirmed to be suffering from a malignant hematological disease. These false diagnoses were associated with the use of imaging methods only (2 cases) or cytology only (1 case), lack of double, independent pathological investigations (2 cases) or immunophenotyping (2 cases) and the occurrence of an unrecognized rare tumor in a hospital with a small patient turnover (1 case). The discovered 11 occult primaries (4 lung, 3 breast, 2 hypopharynx and 1 base of the tongue carcinomas and 1 non-Hodgkin lymphoma) led to a 28% diagnostic efficacy of PET (11/39 malignant pathological reports). This efficacy is doubled (60%) if PET reveals < or = 5 malignant lesions and the locations of the pathological foci are tumor-specific. We suggest PET investigations in the search for occult primaries following a controlled pathological diagnosis and the failure of conventional diagnostic procedures.

[PET scan in patients with epipharyngeal tumors]. / Epipharynx-daganatok PET-vizsgálata.

Whole-body FDG PET examinations in 10 cases of epipharyngeal tumour (8 males, 2 females, mean age: 48 years) have been performed since January 1999. The PET examinations were aimed at the accurate staging, follow-up of the patients after the treatment, identification of recurrencies and localization of the unknown primary tumor. Functional imaging resulted in "upstaging" in 3 patients as compared to staging by the conventional diagnostic tools. Four additional patients with hyperplastic epipharyngeal tissue were investigated for occult primary cancer after negative results of multiple excisions, resulting in one case of primary epipharyngeal cancer. Correct staging, early detection of recurrencies, localization of occult primary tumor and the better post-therapeutic assessment of epipharyngeal masses all facilitate a more reasonable therapeutic approach, which may improve survival results.