Elevation of plasma osteopontin level in patients with undifferentiated nasopharyngeal carcinoma.

AIMS: We evaluated the clinicopathologic relevance of plasma osteopontin (OPN) level in nasopharyngeal carcinoma patients. METHODS: Seventy-two plasma samples were collected from patients with undifferentiated nasopharyngeal carcinoma (NPC) before radiotherapy. Plasma OPN level was determined by quantitative sandwich enzyme immunoassay. The plasma OPN level was evaluated for its clinicopathologic relevance. RESULTS: The mean plasma OPN level was significantly higher in NPC patients than in normal controls (184.66 vs 75.89 ng/ml, p<0.001). In addition, high OPN level was found in the patients with advanced cancer and was correlated with neck node metastasis (p<0.05). CONCLUSIONS: Our findings indicated a potential role of OPN in the pathogenesis and nodal metastasis of undifferentiated NPC.

The study of p16 and p15 gene methylation in head and neck squamous cell carcinoma and their quantitative evaluation in plasma by real-time PCR.

Epigenetic silencing of the p16 and p15 genes by promoter methylation are commonly observed in human epithelial malignancies, including head and neck squamous cell carcinomas (HNSCC). In this study, a methylation-specific polymerase chain reaction (MSP) was used to evaluate the methylation status of the p16 and p15 genes in 73 HNSCC surgical specimens. p16 and p15 gene methylation was also examined in 29 paired metastatic lymph nodes and 29 paired histologically, normal resection margin mucosae. The quantity of cell-free methylated p16 and p15 DNA in the plasma samples of 20 HNSCC patients and 24 healthy controls was also examined using a fluorescence-based real-time PCR assay. The frequencies of p16 and p15 methylation in the primary tumour were 49% and 60%, respectively. Concordant methylation of p16 and p15 in tumour samples and metastatic lymph nodes was found in 59 and 38% of cases, respectively. A significantly higher prevalence of p15 methylation was found in histologically-normal surgical margin epithelia of HNSCC patients with chronic smoking and drinking habits compared with non-smokers and non-drinkers. In addition, methylated p16 and p15 DNA levels were significantly higher in the plasma of HNSCC patients (mean 56 copies/ml plasma and 65 copies/ml plasma, respectively) compared with normal controls (mean 6 copies/ml plasma and 16 copies/ml plasma, respectively). In conclusion, promoter methylation of the p16 and p15 genes is involved in the pathogenesis of HNSCC and may be related to chronic smoking and drinking. The differential levels of methylated p16 and p15 DNA in plasma might be potential useful markers in screening high-risk populations for early HNSCC and monitoring their treatment response.

Nonhematologic malignancies after allogeneic hematopoietic stem cell transplantation: incidence and molecular monitoring.

Survivors of allogeneic hematopoietic stem cell transplantation (HSCT) are at a life-long increased risk of secondary nonhematologic malignancies. In 615 adult Chinese allogeneic HSCT patients, nine developed nonhematologic malignancies. The 5-year cumulative incidence was 6.1%, 4.5 times the background cancer incidence. Early-onset (within first 6 months) and late-onset (>3 years) subtypes were observed. Secondary cancers included hepatocellular carcinoma, oral and esophageal squamous cell tumors and lung adenocarcinoma in a female nonsmoker. The spectrum reflected local cancer epidemiology, which was different from Western populations. The pathogenesis might be related to acceleration of pre-existing cancers (early-onset type), or prolonged immunosuppression (late-onset type). DNA chimerism studies showed that all tumors were recipient-derived. In the plasma, DNA in all cases was apparently donor-derived, although aberrantly methylated p15 was detectable in a patient with a p15-methylated secondary cancer, implying that minute quantities of tumor (and therefore recipient) derived DNA might be present.

A comparative study of the clinicopathological significance of E-cadherin and catenins (alpha, beta, gamma) expression in the surgical management of oral tongue carcinoma.

PURPOSE: E-cadherin and catenins are important epithelial adhesion molecules in normal epithelium. Loss of E-cadherin-catenin adhesion is an important step in the progression of many epithelial cancers. E-cadherin and catenins expression in carcinoma of the tongue were evaluated in relation to their clinicopathological features and prognostic values. METHOD: Immunohistochemical staining was carried out with E-cadherin and (alpha, beta, gamma)-catenin monoclonal antibodies for 85 surgical specimens of oral tongue carcinoma, nine matched metastatic lymph nodes, and seven locally recurrent tumours. RESULTS: There was under-expression in 85% of E-cadherin, 94% of alpha-catenin, 89% of beta-catenin, and 83% of gamma-catenin in the primary tumours. There was no correlation of E-cadherin/catenin expression with sex, age, cancer stage, and differentiation. Nodal metastasis was found in 68% of patients with weak expression of gamma-catenin compared with 9% with strong expression in primary tumours (chi-square, P = 0.02). E-cadherin was a significant prognostic factor for survival and recurrence; patients with weak E-cadherin expression had 53% 5-year survival compared with 85% with strong expression (Wilcoxon, P = 0.0159). CONCLUSIONS: Both E-cadherin and catenins were highly under-expressed in oral tongue carcinoma, metastatic lymph node, and recurrent tumour. gamma-catenin had predictive value for nodal metastasis. E-cadherin was, however, a more important prognostic factor for recurrence and survival.

Cancer of the larynx in Hong Kong: a clinico-pathological study.

Laryngeal cancer is a relatively common cancer in Hong Kong when compared with other cities over the world. The purpose of this study is to characterize and identify the clinico-pathological features of patients with laryngeal cancer being resected or autopsied in our hospital for the years 1973 to 1992. The peak age at presentation of 451 patients (408 males, 43 females) with primary laryngeal cancer resected was 62 years old and 1.6% of patients were under 40. The incidence increased with age in both sexes. The patients were noted to be ageing steadily in the 20-year study period. Most patients (30%) had tumours involving both the supra-glottis and glottis. Histological examination revealed that the cancers comprised squamous cell carcinomas (98.3%), spindle cell carcinoma (0.7%), adenoid cystic carcinoma (0.2%), mucoepidermoid carcinoma (0.2%), atypical carcinoid (0.2%) and chondrosarcoma (0.4%). Most cases of squamous cell carcinoma were moderately differentiated (67.3%). Poorly differentiated squamous cell carcinomas were more often noted in females. Forty-six laryngeal cancers were noted in the study period giving an autopsy incidence of laryngeal cancers of 0.46%. Distant metastases were found in 50% of these autopsied cases. The metastatic lesions were found in the lung (43%), liver (18%), diaphragm/pleura (18%), kidney (9%), bone (7%), heart (5%), spleen (2%), nostril (2%) and small intestine (2%). The results indicate that there are different histological subtypes of laryngeal cancer in Hong Kong Chinese and they share similar epidemiological characteristics with those reported in other studies.

Expression of p53 in recurrent nodal metastasis from nasopharyngeal carcinoma (NPC).

This study reports the incidence of p53 expression in 40 patients with recurrent nodal metastasis from nasopharyngeal carcinoma (NPC) and its prognostic value in this group of patients. Immunohistochemical staining using monoclonal antibody specific for human p53 protein was performed on the tumour-bearing nodes from 40 patients. The results were divided into four grades (I, negative; II, < 10% of cells positive; III, 10-50% of cells positive; and IV, > 50% of cells positive). The staining scores were correlated with histological tumour types, subsequent recurrence and survival. All patients had undergone neck irradiation. Lymph node specimens from six patients (15%) showed positive staining of nuclear p53 protein. The distribution among the different grades was: three (7.5%) for II, two (5%) for III and one (2.5%) for IV. Patients with p53-overexpressed tumours had a significantly higher number of tumour-bearing lymph nodes. There was no correlation of p53 expression with histological tumour types, second tumour recurrence and survival. Expression of p53 appears to be uncommon in patients with recurrent nodal metastases in NPC. It did not have prognostic value in this particular series of patients.

Prospective randomized study of post-operative chemotherapy with levamisole and UFT for head and neck carcinoma.

AIMS: A prospective randomized study was conducted to evaluate the benefit of adjuvant levamisole/UFT (futraful and uracil) chemotherapy in head and neck squamous cell carcinoma. METHODS: Sixty-five patients with stage III and IV squamous cell carcinomas of oral cavity, oropharynx, hypopharynx and larynx with no distant metastasis were randomized for the chemotherapy study. Thirty-one patients were randomized for chemotherapy and two of them were subsequently excluded. In this study, a total of 29 patients on levamisole/UFT therapy and 34 patients on the control group were analysed. The main outcome was measured by the 5-year disease-free actuarial survival rate. RESULTS: The rates of distant metastasis were 10% for chemotherapy group and 32% for control group (P=0.06). The 5-year disease-free actuarial survival rates for patients with and without adjuvant chemotherapy were 57% and 39% respectively (P=0.207). CONCLUSIONS: A trend of better distant control in head and neck cancer patients with post-operative adjuvant oral chemotherapy was observed. The side effects were minimal. However, there was no statistically significant improvement in the overall long-term survival. It may be of value to conduct a large-scale multi-centre prospective randomized study to verify the efficacy of levamisole and UFT as post-operative adjuvant chemotherapy for the control of distant metastasis in high-risk population.

Comprehensive analysis of nodal recurrence of advanced laryngeal carcinoma following surgery.

The problems of nodal recurrence after surgical treatment of T3-4 laryngeal carcinoma were analysed. There were 133 N0 and 66 N+ patients. The 5-year actuarial nodal recurrence rate of N0 patients was 18% and N+ patients was 31%. Nodal recurrence was the commonest site of recurrence. The sites of nodal recurrence of N0 patients were at the level II, III, and IV nodes. Both ipsilateral and contralateral nodal recurrences were common. Of those patients who developed nodal recurrence, 63% patients were feasible for surgical salvage. Surgical salvage with radical neck dissection was the preferred treatment for nodal recurrence with 38% 5-year survival rate. The 'watchful waiting policy' in the management of N0 neck is an acceptable option with eventual nodal failure rate of 10% after surgical salvage. Close follow-up of patients is mandatory for the early detection of surgically salvageable nodal recurrence.

Clinicopathologic significance of plasma matrix metalloproteinase-2 and -9 levels in patients with undifferentiated nasopharyngeal carcinoma.

UNLABELLED: Increased in plasma pro-MMP2 and pro-MMP9 levels in patients with advanced stage NPC were observed. Plasma pro-MMP2 is a significant independent prognostic marker for undifferentiated NPC. AIM: Upregulation of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) expression is observed in many cancers and high level of these proteins are found in peripheral blood of many cancer patients. In this study, we aimed at evaluating the plasma pro-MMP2 and pro-MMP9 pro-enzymes (pro-MMP2 and pro-MMP9) levels and their clinical significances in patients with undifferentiated nasopharyngeal carcinoma (NPC). METHODS: The plasma pro-MMP2 and pro-MMP9 levels were measured in 40 NPC patients and 40 normal individuals by enzyme linked immunosorbant assay. RESULTS: By using the Cox-regression model, a high pro-MMP2 level was found to be significantly correlated with poorer survival. Patients with plasma pro-MMP2 below 650 ng/ml had higher 5-year survival rate of 89%, compared with 50% for patients with plasma pro-MMP2 above 650 ng/ml. CONCLUSIONS: A high level of plasma pro-MMP2 was associated with poor survival of NPC patients independent of sex, age and stage.

Clinicopathologic significance of bcl-2 expression in the surgical treatment of oral tongue carcinoma.

AIM: There is still controversy on the incidence of positive expression of bcl-2 and its prognostic significance for oral tongue carcinoma patients who are treated by surgery. The present study aims at resolving the controversy on the clinicopathologic significance of bcl-2 in a well selected group of patients who satisfy the recruitment criteria: (1) oral tongue carcinoma, (2) squamous cell carcinoma, (3) primary surgical treatment. METHOD: Bcl-2 expression was studied by immunohistochemistry on glossectomy specimens of 73 patients. The expression of bcl-2 was correlated with clinicopathologic data. RESULTS: Of the 73 tumours, 11% had positive expression of bcl-2. Bcl-2 expression was not significantly correlated with tumour grade, stage, nodal metastasis and survival. CONCLUSION: Bcl-2 expression played a minor role in oral tongue carcinoma. It had no significant correlation with tumour grade, stage and nodal metastasis. It also had no prognostic value on survival for patients who were treated by primary surgery.

Risk factors of tracheostomal recurrence after laryngectomy for laryngeal carcinoma.

BACKGROUND: Tracheostomal recurrence after total laryngectomy for laryngeal carcinoma has a poor prognosis. The independent risk factors of tracheostomal recurrence are, however, not well documented. METHODS: This is a multivariate analysis of the risk factors of tracheostomal recurrence after total laryngectomy for 322 laryngeal squamous cell carcinomas. The factors included in the analysis were sex, age, tumor stage, sites of tumor involvement, preoperative airway obstruction, preoperative tracheostomy, extent of surgical resection, radiotherapy, and pathological resection margin. RESULTS: Seventeen (5%) patients developed tracheostomal recurrence. Univariate analysis showed that preoperative airway obstruction, subglottic involvement, and postcricoid extension were significant factors associated with tracheostomal recurrence. Multivariate analysis using logistic regression method showed that both subglottic and postcricoid involvement were independent predisposing factors for tracheostomal recurrence. The tracheostomal recurrence rates were 2% in patients without the risk factor and 10% in patients with the presence of one or both risk factors. CONCLUSIONS: Subglottic and postcricoid involvement were independent risk factors for tracheostomal recurrence.

A comparison of the prognostic significance of tumor diameter, length, width, thickness, area, volume, and clinicopathological features of oral tongue carcinoma.

BACKGROUND: The present study aims at evaluation of the prognostic value of tumor size including diameter, length, thickness, width, area, and volume in the prediction of nodal metastasis, local recurrence, and survival of oral tongue carcinoma. The results will have important implications for the management of patients. METHODS: Eighty-five glossectomy specimens of oral tongue carcinoma were serially sectioned in 3 mm thickness for the tumor size evaluation with computer image analyzer. RESULTS: Among all the tumor size parameters being evaluated, tumor thickness was the only significant factor for the prediction of local recurrence, nodal metastasis, and survival. With the use of 3 mm and 9 mm division, tumor of up to 3 mm thickness has 10% nodal metastasis, 0% local recurrence, and 100% 5-year actuarial disease-free survival; tumor thickness of more than 3 mm and up to 9 mm has 50% nodal metastasis, 11% local recurrence, and 77% 5-year actuarial disease free survival; tumor of more than 9 mm has 65% nodal metastasis, 26% local recurrence, and 60% 5-year actuarial disease-free survival. CONCLUSIONS: Tumor thickness should be considered in the management of patients with oral tongue carcinoma.

Clinicopathological analysis of elective neck dissection for N0 neck of early oral tongue carcinoma.

BACKGROUND: The study aims at evaluation of the efficacy of elective neck dissection as a staging and therapeutic procedure for N0 neck of early carcinoma of the oral tongue by whole organ serial sectioning. METHODS: There were 50 stage I and II patients. The neck dissection specimens were whole organ sectioned in 3-mm intervals for the evaluation of nodal metastasis. RESULTS: There were 18 (36%) patients with subclinical nodal metastasis. The total number of metastatic nodes were 31 (1%) among all 2,826 nodes being examined. The metastatic foci had a median size of 3 mm and occupied a median of 6% of the cross sectional area of the involved nodes. The ipsilateral level II nodes were the commonest (26%) site of metastasis. Metastatic nodes were present in 34% patients who had negative preoperative radiological assessment and in 20% patients who had negative intraoperative frozen section sampling of neck nodes. Patients with subclinical nodal metastasis had a high incidence of regional recurrence (62%) and low survival (27%) when postoperative radiotherapy was not given after elective neck dissection. CONCLUSIONS: Ipsilateral level I,II,III neck dissection is an adequate diagnostic procedure for staging of the N0 neck of early oral tongue carcinoma. Its diagnostic role cannot be replaced by the available pre-operative radiological screening and intra-operative frozen section sampling. However, elective selective neck dissection is an effective but not adequate therapeutic procedure, and post-operative adjuvant radiotherapy and chemotherapy have to be considered for all pathologically positive necks.

Critical appraisal of watchful waiting policy in the management of N0 neck of advanced laryngeal carcinoma.

OBJECTIVE: To analyze the problem of nodal recurrence of N0 neck advanced laryngeal carcinoma. DESIGN: Retrospective analysis. SETTING: Hospital referral center. PATIENTS: One hundred thirty-three patients with cancer stages T3-T4, N0, M0 who had total laryngectomy between January 1981 and December 1990. MAIN OUTCOME MEASURE: Nodal recurrence. RESULTS: Of the 11 patients who had elective radical neck dissections, there was no nodal recurrence. Of the other 122 patients who had no elective neck dissection, 19 patients (16%) developed nodal recurrence and all nodal recurrence was at levels II, III, and IV. Twelve patients (63%) underwent salvage radical neck dissection for nodal recurrence and they had a 38% adjusted 5-year actuarial survival rate. Of these 122 patients who had no elective neck dissection for the N0 neck, 12 patients (10%) eventually died of nodal recurrence. CONCLUSIONS: The watchful waiting policy is a satisfactory management option of N0 neck of advanced laryngeal carcinoma.

Assessment of tracheoesophageal speech in a tonal language. A prospective study.

BACKGROUND: Tracheoesophageal puncture followed by insertion of a voice prosthesis is an increasingly popular method for voice rehabilitation after total laryngectomy. OBJECTIVE: To perform a functional assessment of voice produced by means of the Blom-Singer valve in a tonal language (Cantonese). DESIGN: Prospective study. SETTING: Hospital referral center. MAIN OUTCOME MEASURE: A 5-point scoring scale was adopted for 15 test items of speech assessment grouped into 4 categories: phonatory skills, articulation, additional factors, and general judgment. The sum of the scores for the 15 items was the final speech score. The final speech score was rated as poor, satisfactory, or excellent if it was in the range of less than 30, 31 to 45, or 46 to 75, respectively. RESULTS: Forty-four users of the Blom-Singer valve who had undergone total laryngectomy and primary tracheoesophageal puncture were available for functional assessment. The final speech score was poor in 2 patients (5%), satisfactory in 4 (9%), and excellent in 38 (86%). CONCLUSION: Chinese patients can speak satisfactory tonal language with the Blom-Singer voice prosthesis.

Submucosal tumor extension in hypopharyngeal cancer.

OBJECTIVES: To study the incidence and extent of submucosal tumor extension in hypopharyngeal cancer and to evaluate the impact on the tumor recurrence and overall survival rates. METHODS: Fifty-seven resected specimens of hypopharyngeal cancer were studied in detail from January 1986 to December 1989 by use of the whole-organ, step-serial sectioning technique. RESULTS: Three types of submucosal tumor extension could be identified. Type I extension was characterized by a tumor with a smooth round contour that extended submucosally. The mucosa was thereby elevated and was detectable on gross inspection at operation. In type II extension, tongues and islands of tumor infiltrated within the submucosa, and these were not noticeable on gross examination. Skip metastasis in the submucosa where the submucosal tumor was completely separated from the main tumor bulk was classified as type III extension. Thirty-three patients (58%) had submucosal tumor extension. The frequencies (and extents of submucosal tumor extension) in the superior, medial, lateral, and inferior directions were 16% (3-10 mm), 37% (2-37 mm), 26% (2-37 mm), and 28% (3-35 mm), respectively. Two thirds of the submucosal extension was type I (22 of 33), and only 1 patient had a true skip lesion submucosally (type III extension). Type II submucosal extension was found in one third of the patients (11 of 33). This occurred significantly more often in the patients who had received radiotherapy before surgery (82% [9/11]; P < .001; 95% confidence interval, 1.28-4.44). The presence of submucosal tumor extension had no effect on the tumor recurrence and overall survival rates. CONCLUSIONS: The incidence of submucosal tumor extensions in hypopharyngeal cancer is high (58%), but most (67%) of them can be detected grossly at operation. The presence of submucosal tumor extension does not adversely affect the survival and tumor recurrence rates.

Results of surgical salvage for radiation failures of laryngeal carcinoma.

The results of surgical salvage of radiation failures of laryngeal carcinoma were reviewed. There were 167 stage T3 and T4 patients. The operative mortality was 7%. The complication rates were 8% wound infection, 13% chest complication, and 25% anastomotic leakage. After the first salvage operation, pharyngeal recurrence developed in 28 (18%) patients. Seven (25%) patients were feasible for second salvage operation, and none of them had further local recurrence. There were 9 (5%) tracheostomal recurrences. Of the 126 N0 patients, 23 (18%) had nodal recurrence, and only 5 of the nodal recurrences were feasible for salvage by radical neck dissection. All 41 node-positive patients underwent radical neck dissection, and 9 (23%) had nodal recurrence. Of the 126 node-negative patients, 19 (15%) had distant metastasis. Of the 41 node-positive patients, 18 (44%) had distant metastasis. The node-positive patients had a significantly high distant failure rate despite locoregional control of tumor. The adjusted 5-year survival rate of T3-4N0M0 was 45%, and that of T3-4N + M0 was 22%.

Prospective randomized study of thrice weekly six-month and nine-month chemotherapy for cervical tuberculous lymphadenopathy.

The aim of this study is to compare the efficacy of a thrice weekly 6-month regimen, 4S3H3R3Z3/2H3R3 (which consists of an initial 4 months of streptomycin (S), isoniazid (H), rifampicin (R), and pyrazinamide (Z) followed by 2 months of isoniazid and rifampicin), with a thrice weekly 9-month regimen, 4S3H3R3Z3/5H3R3 (which consists of an initial 4 months of streptomycin, isoniazid, rifampicin, and pyrazinamide followed by 5 months of isoniazid and rifampicin), in the treatment of cervical tuberculous lymphadenopathy. A total of 113 patients were recruited between August 1987 and December 1993. Twenty-two patients were excluded from the analysis because of defaulting treatment or modification of regimen. Ninety-one patients were included in the analysis. Forty-three patients were given the 6-month regimen, and 48 patients were given the 9-month regimen. Two (5%) patients of the 6-month regimen and one (2%) patient of the 9-month regimen had primary failure after completion of treatment (relative risk, 2.23; 95% confidence interval, 0.21 to 23.76). Of the 88 patients who had initial clinical remission after completion of treatment, the 5-year actuarial remission rates were 89% for the 6-month regimen and 90% for the 9-month regimen (Wilcoxon, p = 0.44). There were no significant differences of both primary failure rate and 5-year actuarial remission rate of the two regimens. The 6-month regimen is recommended as the initial treatment of tuberculous lymphadenopathy.

Results of surgical salvage of locoregional recurrence of carcinoma of the tongue after radiotherapy failure.

The aim of this study was to evaluate the efficacy of surgical salvage of local and nodal recurrence of carcinoma of the oral tongue after radiotherapy failure. Of the 47 patients in this retrospective review (between 1980 and 1992), there were 25 with local recurrence alone, 11 with locoregional recurrence, and 11 with nodal recurrence alone. There was no operative mortality, and 17% of patients had one or more surgical complications, including wound infection, flap necrosis, anastomotic leakage, and chest infection. Twenty-nine (62%) patients developed recurrences in the head and neck region after the salvage operation, and 9 of them had second surgical salvage operations. At the last follow-up, 53% of patients had died of carcinoma of the tongue and the overall 5-year actuarial survival rate was 43%. The 5-year actuarial survival rates were 39% for local recurrence alone, 27% for locoregional recurrence, and 68% for nodal recurrence alone. Surgical salvage had satisfactory results for patients with oral tongue carcinoma after radiotherapy failure. Close follow-up and early surgical intervention are essential for patients primarily treated with radiotherapy.