Three-dimensional dosimetric evaluation of a conventional radiotherapy technique for treatment of nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: The aim of this study is to evaluate and delineate the deficiencies in conventional two-dimensional (2-D) radiotherapy planning of nasopharyngeal carcinoma (NPC) treatment and to explore the means for improvement of the existing treatment technique aiming at enhancing local tumor control and reducing treatment complications. METHODS AND MATERIALS: Ten patients with NPC sparing the skull base and without intracranial extension or cranial nerve(s) palsy were chosen in the present study. Two sets of CT images for Phases I and II of the radiotherapy treatment were taken with patient immobilized in the flexed-head and the extended-head positions, respectively. Based on the CT images and endoscopic findings, the gross tumor volume (GTV) was defined. The clinical target volume (CTV) circumscribing the GTV was defined according to Ho's (Halnan, K.E. (ed.) Treatment of Cancer. London: Chapman and Hall, 1982. pp. 249-268) description of the organs at risk of tumor infiltration. The planning target volume (PTV) was defined by adding a margin to the CTV which catered for geometrical inaccuracies. The field borders and shields were set at standard distances from certain bony landmarks and were drawn on the simulator radiograph. Data on the beams and shield arrangements were then transferred to the planning computer via a digitizer. By applying 3-D volumetric dose calculation using a commercial three-dimensional (3D) treatment planning computer, the dose-volume-histograms (DVHs) of GTV, CTV, PTV and critical normal organs were generated for both phases of Ho's treatment technique. The same patients were re-planned using a modified Ho's technique which used 3-D beams-eye-view (BEV) in placing the shielding blocks and the same set of DVHs were generated and compared with those obtained from Ho's technique. RESULTS: The median volumes of GTV, CTV and PTV covered by the 95% isodose in Ho's phase I treatment were around 60%. The dose coverage was unsatisfactory in the superior and inferior and the posterolateral regions. In phase II treatment, the median volume of GTV, CTV and PTV covered by the 95% isodose were 99, 96 and 72%, respectively. Even though the dose coverage of the PTV in both phases of treatment were unsatisfactory, radiotherapy with the original Ho's technique had consistently produced good local control for NPC. However, there is potential room for enhancing the local control further because after modifying Ho's technique by using 3-D BEV customization of the treatment portals, the median volume of the target covered by the 95% isodose was defined as V(95). The V(95) of the PTV during the Phase II treatment was improved by 13%. The 90% of the volume of temporo-mandibular joints and parotid glands were both irradiated to 53 Gy and 43.6 Gy of the total prescribed dose of 66 Gy, respectively, in phase I and II treatments. With the addition of a hypothalamus-pituitary shield to Ho's technique, 50% of the volume of optic chiasma and temporal lobes received, respectively, 19.3 Gy and 4.5 Gy. However, small volume of the temporal lobes received a maximum dose (D(max)) of 62.8 Gy (95.2% of 66Gy). Most of the brainstem was shielded from the lateral portals but 5% of its volume received a dose ranging from 25.4 to 50.4Gy. The spinal cord (at C1/C2 level) received a D(max) of 40.8 Gy in phase I and of 4.8 Gy in phase II. After modifying Ho's technique by 3-D BEV customization of the treatment portals, the D(max) to the brainstem, the optic chiasma and the temporal lobes could be reduced by 8, 12 and 5%, respectively. CONCLUSIONS: Our study indicated that the dose-coverage of the PTV in Ho's radiotherapy technique for the early T-stage NPC was less than satisfactory in the superior and inferior and the posterolateral regions. However, in view of the excellent historical local tumor control with Ho's technique, we have to postulate that the present definition of CTV (and hence the PTV after adding margins to the CTV) lacks clinical significance and can be improved. It appears that the inclusion of the entire sphenoid sinus floor and both medial and lateral pterygoid muscles in the CTV is not necessary for maximal tumor control in the absence of clinical/radiological evidence of tumor infiltration of these organs. Ho's technique can be improved by using 3-D BEV to customize the treatment portals with multileaf collimators or blocks.

Final report of a randomized trial on altered-fractionated radiotherapy in nasopharyngeal carcinoma prematurely terminated by significant increase in neurologic complications.

PURPOSE: The aim of the present study was to compare the survival, local control and complications of conventional/accelerated-hyperfractionated radiotherapy and conventional radiotherapy in nonmetastatic nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: From February 1993 to October 1995, 159 patients with newly diagnosed nonmetastatic (M0) NPC with N0 or 4 cm or less N1 disease (Ho's N-stage classification, 1978) were randomized to receive either conventional radiotherapy (Arm I, n = 82) or conventional/accelerated-hyperfractionated radiotherapy (Arm II, n = 77). Stratification was according to the T stage. The biologic effective dose (10 Grays) to the primary and the upper cervical lymphatics were 75.0 and 73.1 for Arm I and 84.4 and 77.2 for Arm II, respectively. RESULTS: With comparable distribution among the T stages between the two arms, the free from local failure rate at 5 years after radiotherapy was not significantly different between the two arms (85.3%; 95% confidence interval, 77.2-93.4% for Arm I; and 88.9%; 95% confidence interval, 81.7-96.2% for Arm II). The two arms were also comparable in overall survival, relapse-free survival, and rates of distant metastasis and regional relapse. Conventional/accelerated-hyperfractionated radiotherapy was associated with significantly increased radiation-induced damage to the central nervous system (including temporal lobe, cranial nerves, optic nerve/chiasma, and brainstem/spinal cord) in Arm II. Although insignificant, radiation-induced cranial nerve(s) palsy (typically involving VIII-XII), trismus, neck soft tissue fibrosis, and hypopituiturism and hypothyroidism occurred more often in Arm II. In addition, the complications occurred at significantly shorter intervals after radiotherapy in Arm II. CONCLUSION: Accelerated hyperfractionation when used in conjunction with a two-dimensional radiotherapy planning technique, in this case the Ho's technique, resulted in increased radiation damage to the central nervous system without significant improvement in efficacy.

Measuring quality of life of Chinese cancer patients: A validation of the Chinese version of the Functional Assessment of Cancer Therapy-General (FACT-G) scale.

BACKGROUND: Few cancer specific quality-of-life (QoL) measures from the West have been translated for use with Chinese-speaking patients, and no substantial validation of these translations with adequately large cohorts has been published previously, to the authors' knowledge. The Functional Assessment of Cancer Therapy-General (FACT-G) is a well-validated QoL instrument that is specific to cancer patients. The scale was translated into Chinese and the psychometric properties of this translated scale (FACT-G [Ch]) were tested with a Chinese sample in Hong Kong, China. METHODS: A total of 1262 Chinese cancer patients were selected in 3 samples from 5 Hong Kong regional hospitals. Quantitative and qualitative data were used to assess the cultural equivalence, factor structure, reliability, and validity of the FACT-G (Ch). RESULTS: Focus group discussions indicated that the FACT-G was seen as covering QoL domains identified as important and relevant to Chinese cancer patients, though in some respects it was seen as having limited scope in this sample. Psychometrically, the factor structure of the FACT-G deviated from that of the original work. The FACT-G (Ch) had acceptable reliability (Cronbach alpha 0.85). The convergent validity of the FACT-G (Ch) with a generic QoL measure (WHOQOL-BREF[HK]) was 0.72 (P < 0.001), and divergent validity showed low correlations of less than 0.15 (P < 0.05) with non-QoL measures. CONCLUSIONS: Focus group data indicated that the FACT-G translation into Chinese was seen as a conceptually relevant and moderately sufficient QoL measure. Psychometrically, the instrument had acceptable properties, but conceptual differences from the original version were suggested. Although more work is needed to increase its adequacy, the translated scale has reasonable utility for use with Chinese populations in clinical settings.

Late radiation injury to the temporal lobes: morphologic evaluation at MR imaging.

PURPOSE: To study the morphologic characteristics of late radiation injury to the temporal lobes of the brain on magnetic resonance (MR) images. MATERIALS AND METHODS: This was a prospective study involving 34 patients (age range, 37-72 years) with known radiation injury to the temporal lobes from radiation therapy administered 2-10 years previously for nasopharyngeal carcinoma MR imaging was performed with T2-weighted gradient- and spin-echo, gradient-recalled echo, T1-weighted spin-echo, fluid-attenuated inversion-recovery, and T1-weighted postcontrast spin-echo sequences. RESULTS: Radiation injury was present in 57 of the 68 temporal lobes. The white matter lesions in radiation-induced injury were predominantly hyperintense on T2-weighted images, but in 37 (65%) of the 57 lobes, foci with heterogeneous signal intensity consistent with necrosis were detected. In the 57 involved lobes, gray matter lesions were detected in 50 (88%); blood-brain barrier disruption based on parenchymal contrast enhancement, in 51 (89%); and hemosiderin deposits, in 30 (53%). There was a significant correlation between white matter necrosis, gray matter lesions, and blood-brain barrier disruption, all of which were located mainly in the inferior temporal lobes that received the highest radiation dose. CONCLUSION: The lesion components of radiation-induced injury to the temporal lobes at MR imaging were more varied than have been previously described. In addition to the classic white matter lesions, gray matter lesions, blood-brain barrier disruption, and hemosiderin deposition also were frequently seen.

The roles of multileaf collimators and micro-multileaf collimators in conformal and conventional nasopharyngeal carcinoma radiotherapy treatments.

The purpose of this work is to study the efficacy and limitations of using standard multileaf collimators (MLCs) and micro-multileaf collimators (mMLCs) in the treatment of nasopharyngeal carcinoma (NPC) by conventional and conformal radiotherapy techniques. The penumbra characteristics of MLC, mMLC, and customized block collimated beams are measured with respect to leaf edge angle, beam energy, treatment depth, and field size and compared with those generated by a commercial three-dimensional planning computer system. Upon verification of the planning system, it is used to evaluate the treatment plans generated with these beam shapers for conventional and conformal NPC treatments. The effective penumbra of a MLC beam is strongly influenced by its edge angle, leaf width, and treatment depth. The suitability of standard MLCs in conventional NPC treatments is determined mainly by the edge angle to be used. For conformal NPC treatments involving six or more fields, dose volume histograms comparable to those of customized beam blocks are obtained with a standard MLC. The mMLC does not have the same restrictions as those on standard MLC but is limited to phase II treatment by its small usable field size. Both standard MLCs and mMLCs can be used to replace customized divergent beam blocks in both conventional and conformal NPC treatments. However, a MLC, due to its larger effective penumbra, may be unsuitable for use in cases when the tumor volumes extend very close to the critical normal structures. A mMLC, on the other hand, is limited by its small maximum field size and can only be used for collimating the facial portals in the second phase treatment.

Two distinct regions of deletion on chromosome 13q in primary nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is rare in most parts of the world, but prevalent in Southern China. Although this disease poses a serious health problem in our population, the genetic alterations that lead to the development of NPC have yet to be defined. In a comparative genomic hybridization (CGH) study on NPC by our group, loss of the long arm of chromosome 13 has been identified as a frequent event. To investigate further the involvement of this genetic alteration in NPC tumorigenesis, we examined 31 primary NPC tumours by LOH analysis with a panel of 13 microsatellite polymorphic markers distributed along the long arm of chromosome 13. It was found that 19/31 tumours (60%) showed LOH for markers on chromosome 13q. The highest frequency of LOH was found at loci D13S133 (53.6%) on 13q14.3 and D13S796 (38.5%) on 13q32-34. Two distinct smallest deletion regions were delineated: the first region between D13S133 and D13S119 at 13q14.3-22, and the second region between D13S317 and D13S285 at 13q31-34. Our findings show that LOH of 13q is a common event in NPC and that at least 2 putative tumour-suppressor loci may be present on 13q. Mapping of the critical regions of these loci suggests that some candidate tumour-suppressor genes on 13q, other than Rb and BRCA2, may be involved in the development of NPC.

Detection of recurrent chromosomal gains and losses in primary nasopharyngeal carcinoma by comparative genomic hybridisation.

Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China but rare in Western countries. To search for genetic alterations in NPC, we examined a series of 20 primary tumours with comparative genomic hybridisation. The identified common chromosomal alterations included gain of chromosomes 1q, 8, 12, 19 and 20 as well as loss of chromosomes 1p, 3p, 9p, 9q, 11q, 13q, 14q and 16q. In concordance with our previous loss of heterozygosity studies in primary NPC, a high incidence of loss was detected on chromosomes 3p (75%), 11q (70%) and 14q (65%). Losses of 9q (60%), 13q (50%) and 16q (40%) were also identified. Novel chromosomal gains were observed on chromosome 12, with a high frequency (70%). Current analysis has revealed a comprehensive profile of the chromosomal regions showing losses and gains in primary NPC. Our findings may provide an entry point for conducting further investigations to locate the putative tumour-suppresser genes and oncogenes that may be involved in the tumourigenesis of NPC.

The significance of keratinizing squamous cell histology in Chinese patients with nasopharyngeal carcinoma.

Six hundred and ninety-three Chinese patients with non-metastatic nasopharyngeal carcinoma (NPC) were treated at one institution under a uniform protocol between 1984 and 1989. The tumour histology of these patients was subjected to a standardized review and classified into two distinct groups of World Health Organization (WHO) type I (keratinizing squamous cell carcinoma) (n = 13) or WHO types II and III (non-keratinizing carcinoma and undifferentiated carcinoma) (n = 662). The differentiation between the two groups was uncertain in 18 patients. The patient characteristics and clinical outcome after a uniform treatment policy of the two groups were not statistically significantly different. The low incidence of WHO type I NPC may account for the lack of prognostic significance of this histological subtype in Chinese populations.

Multidisciplinary management of osteosarcoma: experience in Hong Kong.

All pediatric osteosarcomas treated in our hospital between 1985 and 1995 were reviewed. There were 26 patients, 15 males and 11 females, aged 20 or less at diagnosis. All had limb primaries. Nineteen patients had localized disease and seven presented with metastases. Intensive multiagent chemotherapy was given both pre- and postoperatively. Most patients were treated with the Rosen T10 regimen or its modifications. Only one patient had limb salvage surgery; all others had amputation. With a median follow-up of 74 months, the 5-year disease-free survival among patients with localized disease was 65.2%. Being female and having a high 6-hour postinfusion methotrexate level with a median level greater than 700 mumol/L were good prognostic factors. Three of the seven patients with metastatic disease were alive at 21, 26, and 140 months after diagnosis. All of them had lung secondaries. Survival rates achieved in our center were comparable to those reported in literature. However, our amputation rate was high and further development in expertise for limb salvage treatment is a goal.

Loss of heterozygosity on the long arm of chromosome 11 in nasopharyngeal carcinoma.

Loss of heterozygosity (LOH) on the long arm of chromosome 11 had been reported in many types of solid tumors. In this study, we investigated the LOH patterns of chromosome 11 on 52 primary nasopharyngeal carcinomas using 10 microsatellite polymorphic markers. The results revealed that 28 of the 52 cases (53.8%) demonstrated LOH on at least one of the nine 11q microsatellite loci studied. The highest frequencies of LOH were found at the two loci D11S2000 (36.1%) and D11S934 (34.5 %), both located at 11q22-24. Two distinct regions of deletion were found at 11q, with the first one defined by INT-2 and D11S900 at 11q13.3-22, and the second region located between D11S2000 and D11S934 at 11q22-24. The two deletion regions overlap with the common areas of deletion reported in other tumor types. This suggests the presence of multiple putative tumor suppressor genes on chromosome 11q that may play a role in the development of nasopharyngeal carcinomas.

Breast metastasis in adolescents with alveolar rhabdomyosarcoma of the extremities: report of two cases.

We describe two adolescent girls with alveolar rhabdomyosarcoma arising from extremities who developed bilateral breast metastasis in their clinical course. In both cases, there was widespread systemic disease at initial presentation. Although complete remission was achieved on the 25th week post-chemotherapy initiation, the first patient developed breast metastasis in addition to systemic recurrence on the 44th week and expired. For the second patient, breast metastasis was noted in addition to systemic disease at initial presentation. Aggressive chemotherapy with autologous transplant and radiotherapy were given in addition to bilateral subcutaneous total mastectomy. The patient remained in complete remission 3 months post-therapy. We postulate that adolescent females with alveolar rhabdomyosarcoma of the extremities have a high risk of developing breast metastasis in the pubertal period, and aggressive multidisciplinary treatment is indicated.

Nasopharyngeal carcinoma with metastatic disease to mediastinal and hilar lymph nodes: an indication for more aggressive treatment.

Nasopharyngeal carcinoma (NPC) is a highly chemo- and radiosensitive tumour, distinctive from other head and neck squamous cell carcinomas. Distant metastatic rates correlate directly with T and N stages. The prognosis of metastatic NPC is grave and long term survivors are anecdotal. We encountered an 18-year-old man with locoregionally advanced NPC, who was initially treated with neoadjuvant chemotherapy and radiotherapy, but subsequently relapsed 6 months later in the superior mediastinal and right hilar nodal regions. Further chemotherapy and consolidation radiotherapy resulted in complete remission. He is currently alive and free of disease 5 years and 6 months after the completion of salvage treatment. We recommend aggressive treatment of NPC with isolated intrathoracic nodal relapse and imaging of the mediastinum for non-metastatic Ho's Stage N3 NPC patients.

A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma.

PURPOSE: A prospective randomized trial was conducted to compare chemoradiotherapy against radiotherapy alone in the treatment of locoregionally advanced nasopharyngeal carcinoma. METHODS AND MATERIALS: Eighty-two patients with histologically proven nasopharyngeal carcinoma who had either Ho's N3 staging or any N stage with a nodal diameter of > or = 4 cm were entered. Seventy-seven patients were evaluated for tumor response and survival. The patients were randomized to receive two cycles of cisplatin 100 mg/m2 Day 1,5-fluorouracil 1000 mg/m2 24-h infusion Days 2, 3, and 4 before radical radiotherapy, and four cycles of postradiotherapy chemotherapy (37 patients) or radiotherapy alone (40 patients). All patients received radical radiotherapy to the nasopharynx and neck. The nasopharynx and upper neck were treated to 66 Gy by conventional fractionation and the lower neck to 58 Gy. Booster radiotherapy (7.5 Gy/two fractions/week) was given to any residual nodes after standard radiotherapy. RESULTS: The patient characteristics, including staging, were similar in both arms. The overall response rate to neoadjuvant chemotherapy was 81% (19% complete response, 62% partial response). The rates of radiotherapy for boosting parapharyngeal disease or residual lymph nodes were not significantly different in the two arms. The overall complete response rate to chemoradiotherapy was 100%, and to radiotherapy alone, 95%. Toxicities in the chemoradiotherapy arm were mainly myelosuppression, nephrotoxicity, and nausea and vomiting. The degree of mucositis was not significantly different in the two arms. There was no treatment-related death. The median follow up was 28.5 months. The 2-year overall survival was 80% in the chemoradiotherapy arm and 80.5% in the radiotherapy arm. The 2-year disease-free survival was 68% in the chemoradiotherapy arm and 72% in the radiotherapy arm, without significant difference between the two arms. The locoregional relapse rate, distant metastatic rate, and median time to relapse were also not significantly different between the two arms. CONCLUSION: Despite promising tumor response rates from Phase II trials, this prospective randomized trial has demonstrated no benefit from adjunctive chemotherapy to radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

Perineal Paget's disease: effective treatment with fractionated high dose rate brachytherapy.

A patient with perineal extramammary Paget's disease is described. He was treated successfully with fractionated high dose rate brachytherapy.

A region of homozygous deletion on chromosome 9p21-22 in primary nasopharyngeal carcinoma.

Using 21 microsatellite polymorphic markers spanning both p and q arms, we have performed detailed deletion mapping on chromosome 9 in 18 primary nasopharyngeal carcinomas. All 18 tumors were informative at multiple loci. Eleven of the 18 cases (61%) demonstrated allelic deletion of chromosome 9. Among these 11, 6 cases are likely to be tumors with monosomy of chromosome 9. The other 5 cases demonstrated partial deletion by showing multiple areas of allelic loss. In one of the 5 cases, a homozygous deletion region was identified which includes D9S126, D9S171, and IFNA loci at 9p21-22, situated between loci D9S161 (9p21) and D9S162 (9p21-22). The presence of a homozygous deletion strongly suggests the presence of tumor suppressor gene(s) involved in the tumorigenesis of nasopharyngeal carcinoma. The same region has been reported to include some potential tumor suppressor gene loci in other cancers. This is the first reported finding of frequent genetic loss observed on chromosome 9 in nasopharyngeal carcinomas in addition to allelic loss on chromosome 3p at specific regions. Our results suggest that tumorigenesis and progression of nasopharyngeal carcinomas, like other solid tumors, involves multiple genetic changes associated with the inactivation of tumor suppressor genes.

Patterns of early treatment failure in non-metastatic nasopharyngeal carcinoma: a study based on CT scanning.

Six hundred and twenty-eight patients with non-metastatic nasopharyngeal carcinoma were staged by CT scanning and treated with radical locoregional radiotherapy. Parapharyngeal boost radiation for bulky parapharyngeal involvement, neoadjuvant chemotherapy for bulky nodal metastases, and intracavitary 192Ir treatment for local persistence of tumour after external radiotherapy were also used as appropriate. Forty-eight patients had Ho's (1978) Stage I disease (7.6%), 167 Stage II (26.6%), 312 Stage III (49.7%) and 101 Stage IV (16.1%). At 2 years after treatment, 185 patients (29.5%) had developed recurrence; 112 had distant metastases (60.5%), and 75 had local failure (40.5%). Eighty-three patients had developed distant metastases alone, 73 patients locoregional failure alone and 29 patients had both locoregional and metastatic failure. The overall 2-year actuarial distant and local failure rates were 18.4% and 12.7% respectively. Distant metastasis is the major form of treatment failure which limits early survival. Seventy-four per cent of distant metastases were not associated with locoregional recurrence and had probably arisen from pre-existing occult foci. Our data also suggest that the advent of CT scanning has improved local tumour delineation and radiotherapy planning, and hence local control.

Nasopharyngeal carcinoma: genetic changes, Epstein-Barr virus infection, or both. A clinical and molecular study of 36 patients.

BACKGROUND: The pathogenesis of nasopharyngeal carcinoma has been under intense investigation, especially of its peculiar predominance in southern China. The authors previously reported consistent loss of genetic material on the short arm of chromosome 3 in a few nasopharyngeal carcinoma cases. In this study, the authors examined the genetic changes as well as the presence of Epstein-Barr virus (EBV) genome on 36 nasopharyngeal carcinoma primary biopsy specimens of the undifferentiated type and the correlation of the findings to patients' clinical status. METHODS: The authors examined the DNA from tumor tissue and from matched blood leukocytes of 36 patients who suffered from nasopharyngeal carcinoma by the restriction fragment length polymorphism analysis. The genotyping for EBV was carried out by polymerase chain reaction using primers complementary to both types of EBV and probes specific to EBNA-2A (EBV-A) or EBNA-2B (EBV-B). RESULTS: A consistent deletion at two specific locus of the short arm of chromosome 3 was observed in all informative cases. The authors also found that EBV genome, especially type A, was present in 35 of 36 cases. In the remaining one case, EBV-B was detected. CONCLUSIONS: As the same tumor tissue was used for both genetic and viral studies in each case, the results may represent sequential genetic lesions in the pathogenesis and/or summation of genetic events. Moreover, 7 of 32 informative tumors were from patients of early staging (Stages I and II), which suggests the genetic changes may occur in the early development of nasopharyngeal carcinoma. Difference in allele frequency in specific locus was also noted between Asian and white patients for the first time.

p53 mutation in human nasopharyngeal carcinomas.

Nasopharyngeal carcinoma (NPC) is the third most common cancer in the southern provinces of China, but a rare cancer in other parts of the world. Epidemiological studies suggested a multifactorial etiology of NPC involving infection of Epstein Barr virus (EBV), genetic predisposition, environmental factors, such as consumption of salted fish, and other unknown factors. p53 mutation is a common event in many forms of human cancers but its possible involvement in the pathogenesis of NPC has not been examined. The presence of p53 mutation in NPC is studied by the sensitive PCR-SSCP analysis and direct DNA sequencing method. The frequent sites of p53 mutation (exons 4 to 8) reported in other human tumors were studied. Thirty-eight biopsied tumors of NPC and 4 NPC cell lines were examined for the presence of p53 mutation. No mutation of p53 resulting in change in amino acid sequence of the encoded p53 protein was identified in any of the biopsies tumors. RFLP studies of the biopsied materials of NPC also revealed no loss of heterozygosity at chromosome region 17p13 in 15 out of 15 informative cases, which further supports the conclusion that p53 mutation is an infrequent event in NPC. Apparently, p53 mutation has no significant role in the pathogenesis of this special group of human cancers. However, p53 mutation is frequently observed in cell lines derived from the primary NPC tumors. All the three NPC cell lines examined carry a missense p53 mutation, suggesting that mutation of the p53 gene may confer growth advantage to the tumor cells to become established in culture.

Loss of heterozygosity on the short arm of chromosome 3 in nasopharyngeal carcinoma.

A consistent loss of constitutional heterozygosity within a specific chromosome locus in a tumor type is suggestive of a tumor suppressor gene important in the genesis of that tumor. We studied whether such genetic alterations are involved, in the development of nasopharyngeal carcinoma (NPC). Tumor and matched blood leukocytes DNA from eleven Hong Kong Chinese patients with primary NPC stages I to IV were subjected to restriction fragment length polymorphism (RFLP) analysis using chromosome 3-specific polymorphic probes. Such probes are assigned to chromosomal region 3p25 (RAF-1), 3p24-22.1 (ERBA beta), 3p21 (DNF15S2), 3p14 (D3S3), and 3q12 (D3S1). The breakpoint varied among tumors, ranging in extent from 3p21-14. However, 100% frequency of complete loss of heterozygosity was observed at two chromosomal loci: RAF-1 locus (ten of ten cases at 3p25) and D3S3 locus (nine of nine cases at 3p14), in all evaluable NPC patients, suggesting the presence of putative tumor suppressor gene(s) within or close to these defined regions. The observed consistent deletion of alleles on the short arm of chromosome 3 in the NPC cases, which is in line with our previously reported and present cytogenetic findings, may represent a critical event in the multistep genesis of NPC. The present report also identifies defined loci for linkage studies on NPC families.