W. H. Lau

Papillary microcarcinoma of the thyroid-Prognostic significance of lymph node metastasis and multifocality.

It is known that patients with papillary microcarcinoma (PMC) of the thyroid gland have a very favorable prognosis. The rising incidence of PMC among papillary thyroid carcinoma (PTC) necessitates the identification of prognostic factors and the formulation of treatment protocols.

Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients.

PURPOSE To study the clinical features and outcome for primary non-Hodgkins lymphomas of the nose/nasopharynx (NNP-NHLs) according to immunophenotype. PATIENTS AND METHODS One hundred thirteen Chinese patients with primary NNP-NHLs that belonged to the categories E, F, G, or H according to the Working Formulation (WF), with full immunophenotypic data and complete clinical follow-up data, were analyzed in this retrospective study. RESULTS Ninety (79.6%) patients had localized (stage I or II) disease, while 23 (20.4%) had stage III or IV disease. The lymphomas in 51 (45.1%), 24 (21.3%), and 38 (33.6%) patients showed natural killer (NK)/T- (CD56-positive), T-cell, and B-cell immunophenotype, respectively. Seventy-three patients (65.8%) achieved a complete remission, of whom 34 (46.6%) subsequently relapsed. The median follow-up time for those alive was 88 months. The 5-year actuarial disease-free and overall survival rates were 34.4% and 37.9%, respectively. Multivariate analysis showed that only stage and immunophenotype were significant for survival. NK/T lymphomas were distinctive among the three immunophenotypes in the following aspects: the highest male-to-female ratio, more frequent involvement of the nasal cavity alone, higher risk of dissemination to the skin, more frequent development of hemophagocytic syndrome, and the worst prognosis (overall median survival, 12.5 months). CONCLUSION The three immunophenotypes studied are shown to exhibit different clinical patterns. Since the NK/T phenotype carries the worst prognosis, patients who present with NNP-NHL should have their tumors analyzed for CD56 expression.

Preliminary Results of a Randomized Study on Therapeutic Gain by Concurrent Chemotherapy for Regionally-Advanced Nasopharyngeal Carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group

PURPOSE This randomized study compared the results achieved by concurrent chemoradiotherapy (CRT) versus radiotherapy (RT) alone for nasopharyngeal carcinoma (NPC) with advanced nodal disease. PATIENTS AND METHODS Patients with nonkeratinizing/undifferentiated NPC staged T1-4N2-3M0 were randomized to CRT or RT. Both arms were treated with the same RT technique and dose fractionation. The CRT patients were given cisplatin 100 mg/m2 on days 1, 22, and 43, followed by cisplatin 80 mg/m2 and fluorouracil 1,000 mg/m2/d for 96 hours starting on days 71, 99, and 127. RESULTS From 1999 to January 2004, 348 eligible patients were randomly assigned; the median follow-up was 2.3 years. The two arms were well-balanced in all prognostic factors and RT parameters. The CRT arm achieved significantly higher failure-free survival (72% v 62% at 3-year, P = .027), mostly as a result of an improvement in locoregional control (92% v 82%, P = .005). However, distant control did not improve significantly (76% v 73%, P = .47), and the overall survival rates were almost identical (78% v 78%, P = .97). In addition, the CRT arm had significantly more acute toxicities (84% v 53%, P < .001) and late toxicities (28% v 13% at 3-year, P = .024). CONCLUSION Preliminary results confirmed that CRT could significantly improve tumor control, particularly at locoregional sites. However, there was significant increase in the risk of toxicities and no early gain in overall survival. Longer follow-up is needed to confirm the ultimate therapeutic ratio.

Most nasal/nasopharyngeal lymphomas are peripheral T-cell neoplasms

Eleven consecutive cases of nasal/nasopharyngeal lymphoma were studied histologically and with a panel of monoclonal antibodies. The disease showed a male predominance and occurred over a wide age range, with a median of 52 years. Five patients had midfacial destructive disease, and six had gross tumor masses involving the nose/nasopharynx. Three cases were classified as small cleaved cell, two cases as mixed cell, five cases as large cell, and one case as immunoblastic lymphoma. Those belonging to the first two categories also satisfied the diagnostic criteria of so-called polymorphic reticulosis. Epithelial invasion, angioinvasion, and coagulative necrosis were demonstrated in seven, eight, and nine cases respectively. Immunohistochemical studies confirmed that the atypical cells of all 11 cases exhibited Tcell markers. All but one case had lost one or more T-cell markers associated with peripheral T cells, particularly Tl and T3. Loss of T-cell markers in the five cases histologically consistent with polymorphic reticulosis provided further support to indicate that the lesion was neoplastic. A significant proportion of cases also expressed the activated T-cell markers 12 (HLA-DR) and interleukin- 2 receptor (IL-2R1).

Identification of serum amyloid A protein as a potentially useful biomarker to monitor relapse of nasopharyngeal cancer by serum proteomic Profiling

Purpose: Nasopharyngeal cancer (NPC) is a common cancer in Hong Kong, and relapse can occur frequently. Using protein chip profiling analysis, we aimed to identify serum biomarkers that were useful in the diagnosis of relapse in NPC. Experimental Design: Profiling analysis was performed on 704 sera collected from 42 NPC patients, 39 lung cancer patients, 30 patients with the benign metabolic disorder thyrotoxicosis (TX), and 35 normal individuals (NM). Protein profile in each NPC patient during clinical follow up was correlated with the relapse status. Results: Profiling analysis identified two biomarkers with molecular masses of 11.6 and 11.8 kDa, which were significantly elevated in 22 of 31 (71%) and 21 of 31 (68%) NPC patients, respectively, at the time of relapse (RP) as compared with 11 patients in complete remission (CR; RP versus CR, P = 0.009), 30 TX (RP versus TX, P < 0.001), or 35 NM (RP versus NM, P < 0.001). The markers were also elevated in 16 of 39 (41%) lung cancer patients at initial diagnosis. By tryptic digestion, followed by tandem mass spectrometry fragmentation, the markers were identified as two isoforms of serum amyloid A (SAA) protein. Monitoring the patients longitudinally for SAA level both by protein chip and immunoassay showed a dramatic SAA increase, which correlated with relapse and a drastic fall correlated with response to salvage chemotherapy. Serum SAA findings were compared with those of serum Epstein-Barr virus DNA in three relapsed patients showing a similar correlation with relapse and chemo-response. Conclusions: SAA could be a useful biomarker to monitor relapse of NPC.

Randomized Trial of Radiotherapy Plus Concurrent–Adjuvant Chemotherapy vs Radiotherapy Alone for Regionally Advanced Nasopharyngeal Carcinoma

BACKGROUND Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.

Detection of Epstein-Barr Viral RNA in Malignant Lymphomas of the Upper Aerodigestive Tract

Recent studies have suggested a probable etiologic association between Epstein-Barr virus (EBV) and nasal lymphomas, irrespective of geographic location. This study was performed to investigate the strength of association of EBV with non-Hodgkins lymphomas of the upper aerodigestive tract, based on a large series of cases that have been thoroughly immunophenotyped on frozen tissues. A sensitive in situ hybridization technique was used to detect EBV encoded RNA (EBER) in paraffin sections. Among 30 cases of nasal/nasopharyngeal T-cell lymphoma, 25 (83.3%) were EBER-positive. In the positive cases, most of the neoplastic cells showed strong nuclear signals. Further analysis of this group of tumors showed that all 21 cases (100%) with a CD56+ CD3-phenotype were EBER positive, whereas four of nine cases (44.4%) with a CD56-negative immunophenotype were positive. Only one of 10 cases (10%) of nasal/nasopharyngeal B-cell lymphoma was EBER positive; the positive case was a diffuse mixed-cell lymphoma and could not be distinguished morphologically from the negative cases. Among the 21 cases of lymphoma of the tonsils and back of the tongue (20 B-lineage and one T-lineage), none was EBER positive. In the normal mucosa of the nose/nasopharynx or tonsil (20 cases studied), only very rare EBER-positive small lymphocytes were found in two cases. The almost exclusive detection of EBER in nasal/nasopharyngeal T-cell neoplasms among the lymphomas of the upper aerodigestive tract suggests that EBV probably plays an etiologic role in the pathogenesis of this group of tumors and is not simply a passenger virus, and neither is this merely a site-dependent phenomenon in view of the weak association with nasal/nasopharyngeal B-cell lymphoma.

Clinical diagnosis of late temporal lobe necrosis following radiation therapy for nasopharyngeal carcinoma

This is a preliminary report of 102 patients with clinical diagnosis of late temporal lobe necrosis after radical radiation therapy for nasopharyngeal carcinoma during 1964 to 1983. Histologic verification was available in 12 cases. All but three patients had been treated in our institute using schedules with doses larger than the conventional 200 cGy per fraction. The incidence rate was 1.03%. In our 80 patients with only one course of external irradiation, the doses to the temporal lobes ranged from 1665 to 2127 ret, or 1286 to 1778 brain tolerance unit (btu). The latent interval ranged from 9 months to 16 years. The median observation period is 33 months. The symptomatology, working diagnosis, treatment, and outcome are described. Surgery was hazardous because of the bilaterality of the involvement and exploration for mere verification of diagnosis was unjustified in typical cases. Treatment with corticosteroid achieved durable objective response in 25 (35%) of 72 patients. The importance of early detection and corticosteroid treatment is discussed.

Reirradiation for recurrent nasopharyngeal carcinoma: Factors affecting the therapeutic ratio and ways for improvement

PURPOSE To identify factors for maximizing local salvage and minimizing damages by reirradiation for recurrent nasopharyngeal carcinoma. METHODS AND MATERIALS 654 patients with recurrent nasopharyngeal carcinoma treated by reirradiation during 1976-1992 were retrospectively analyzed. Various fractionation schedules had been used during primary treatment with the total dose ranging from 45.6-70 Gy, fractional dose (at different phases) 1.5-4.2 Gy, and overall time 36-101 days. The gap between the two courses ranged from 0.5-10.6 years. Eighty-two percent of patients were reirradiated with teletherapy, 6% brachytherapy, and 12% with both. For those treated with teletherapy alone, the total dose ranged from 7.5-70 Gy, fractional dose 1.8-5 Gy, and overall time 3-89 days. RESULTS The 5-year actuarial local salvage and complication-free rates were 23% and 52%, respectively. Multivariate analyses showed that the extensiveness of local recurrence was the most significant factor affecting local salvage, while T-stage of primary tumor also influenced prognosis. Choice of method for reirradiation and fractional effect during both courses affected the risk of late complications. For patients treated by teletherapy alone, the hazard of local failure decreased by 1.7% per Biological Effective Dose (assuming alpha/beta ratio = 10) of the second course, while radiation factors during primary radiotherapy had no significant effect. On the other hand, the risk of late complications was predominantly affected by the primary treatment: the hazard increased by 4.2% per Biological Effective Dose (assuming alpha/beta ratio = 3) of the first course, while the corresponding impact of reirradiation failed to reach statistical significance. Length of the gap between the two courses did not affect the outcome. CONCLUSION Early detection of local recurrence and adequate total dose by reirradiation are crucial for improving the chance of local salvage. Combination of teletherapy and brachytherapy should be considered whenever feasible and large fractional dose avoided to minimize late complications. Optimization of biological dose during primary treatment is important.

Effect of Time, Dose, and Fractionation on Temporal Lobe Necrosis Following Radiotherapy for Nasopharyngeal Carcinoma

PURPOSE To study the relative effects of different radiation factors on temporal lobe necrosis (TLN) and predictive accuracy of different biological equivalent models. METHODS AND MATERIALS Consecutive patients (1008) treated radically with four different fractionation schedules during 1976-1985 for T1 nasopharyngeal carcinoma were retrospectively analyzed. All were irradiated by megavoltage photons using the same technique. Their age ranged from 18-84 years, and 92% of patients had complete follow-up. The fractional dose to inferomedial parts of both temporal lobes ranged from 2.5-4.2 Gy, total dose 45.6-60 Gy, and overall time 38-75 days. RESULTS Despite a lower total dose of 50.4 Gy, the 621 patients irradiated with 4.2 Gy per fraction had a significantly higher incidence of temporal lobe necrosis than the 320 patients treated to 60 Gy with 2.5 Gy per fraction: the 10-year actuarial incidence being 18.6% vs. 4.6%, p < 0.001. Multivariate survival analysis showed that fractional effect (product of total dose and fractional dose) was the most significant factor: p = 0.0022, hazard ratio (HR) = 1.044 per Gy2. Overall time and age were both insignificant. The alpha/beta ratio calculated from our data was 2.9 Gy (95% CI: -1.8, 7.6 Gy). Biological effective dose (BED(Gy3)), neuret, and brain tolerance unit all showed strongly significant correlation with the necrotic rate (p < 0.001), and gave similar predictions. The hazard of TLN increased by 14% per Gy3, and it was estimated that 64 Gy (at conventional fractionation of 2 Gy daily) would lead to a 5% necrotic rate at 10 years. Not only did the nominal standard dose (NSD) show the lowest value in terms of log likelihood and standardized HR, but its predictions on TLN deviated markedly from clinically observed rates. CONCLUSION Fractional effect is the most significant factor affecting cerebral necrosis, and overall time has little protective effect. The BED formula, assuming an alpha/beta ratio of 3 Gy, is an appropriate model for predicting late effects on the temporal lobe, and NSD could give seriously misleading predictions.