Expression of epidermal growth factor receptor in glottic carcinoma and its relation to recurrence after radiotherapy

expression of EGFR was determined immunohistochemically in two groups of patients with glottic carcinoma, one that recurred after a full course of radiotherapy and one that did not. Using a 4-graded scale (-, +,++,+++) 80% (12/15) of the recurrent carcinomas had a staining intensity and proportion of stained cells of ++ or more. The same figure for non-recurrent carcinomas was 39% (7/18). The difference is statistically significant (chi-squared with Yates' correction, P &<5). The results indicate that an increased expression of EGFR may influence the rate of recurrence of glottic squamous cell carcinoma after radiotherapy.     

Prognostic significance of EGF receptor expression in early glottic cancer

Objective: A positive relationship between epidermal growth factor receptor (EGFR) expression and radioresistance has been shown both in vitro and in vivo. In a group of 31 patients with early glottic cancer treated with definitive radiotherapy, the relationship of EGFR expression with patient and tumor related parameters were analyzed and the prognostic effect of EGFR expression on local control (LC) was assessed. Material and method: Between 1991 and 2001, 114 patients with early glottic (Tis-T2N0M0) squamous cell carcinoma were treated with radiotherapy at our institution. Among these, 31 patients whose pretreatment pathology specimens were available for immunohistochemical analysis formed the study population. Median age was 64 (46–77). Anterior commissure involvement was evident in 12 (38.7%) patients. Distribution according to T stage was as follows: Tis 6 (19.3%), T1 22 (71%), and T2 3 (9.7%). Histopathological grades of the 25 T1-2 tumors were 10/25 (40%) grade 1, 9/25 (36%) grade 2 and 6/25 (24%) grade 3. Our radiotherapy regimen was 66–70 Gy in 33–35 fractions over 6.5–7 weeks. The median follow-up period was 45 months (range, 5–116). Following immunohistochemical staining, quantitative immunohistochemistry (IHC) was performed by image analysis software and stained tumoral area percentage (STAP) was identified. The cut-off value was ≤5% versus >5%. The relationship of EGFR expression with patient (age) and tumor related (T stage, histopathological grade, and anterior commissure involvement) parameters was evaluated using chi-square test. Prognostic significance of EGFR expression, age, T stage, histopathological grade, and anterior commissure involvement on LC was assessed using log-rank test. Results: No difference was found in EGFR content distribution in relation to age, T stage, histopathological grade, and anterior commissure involvement. In the univariate analysis including age (≤60 versus >60), T stage (Tis and T1 versus T2), histopathological grade (grade 1 and 2 versus grade 3), anterior commissure involvement (present versus absent), and EGFR expression (high versus low), only T stage and EGFR expression were found to be significant prognostic factors affecting LC (P = 0.0006 and P = 0.03, respectively). Conclusion: The results of this series support that EGFR expression is an unfavorable prognostic factor in early glottic carcinomas. For this reason EGFR IHC may be considered for selecting patients for more aggressive therapies (radiotherapy with different fractionation schemes or surgery) or enrollment into trials targeting EGFR signaling pathways.     

Prognostic significance of epidermal growth factor receptor in squamous cell carcinoma of the maxillary sinus

Summary The expression of epidermal growth factor receptor (EGFR) was determined immunohistochemically in two groups of maxillary sinus squamous cell carcinomas, one with recurrences at the primary site after combination therapy with radiotherapy, chemotherapy and/or surgery and one without local recurrences. Using a four-graded scale (-,+,++,+++), 9 of the 10 recurrent carcinomas had a staining intensity and proportion of stained cells of ++ or more. A comparable staining intensity was found in 9 of the 18 non-recurrent carcinomas. This difference is statistically significant (Fisher's exact probability test, P < 0.05). These results indicate that an increased expression of EGFR may influence the recurrence rate of squamous cell carcinoma of the maxillary sinus after combined therapy.     

The role of supracricoid laryngectomy for glottic carcinoma recurrence after radiotherapy failure: a critical review

CONCLUSIONS: In the near future salvage supracricoid laryngectomy (SCL) will be used more extensively for failures of radiotherapy for glottic carcinoma. OBJECTIVES: Primary radiotherapy has been used for patients with early glottic carcinomas in northern Europe and North America for more than half a century. Local recurrences after radiotherapy for glottic malignancies occur in 5-25% for T1 carcinomas and in 15-50% for T2 carcinomas. The classic choice as salvage surgery in cases of glottic squamous cell carcinoma recurrence after irradiation failure is total laryngectomy. The development of extended conservation procedures such as SCL has permitted an increasing number of successful partial laryngectomies that save laryngeal functions after radiotherapy failure. SCL allows the creation of a neo-larynx, permitting both swallowing and speech; in most cases the tracheostoma can be closed. METHODS: The electronic database Pubmed was searched without publication date limits. RESULTS: Considering available data (103 cases), 84.5% of the cases treated with salvage SCL for irradiation failure did not present a new local recurrence; laryngeal recurrences after salvage SCL (15.5%) were successfully treated with total laryngectomy in 66.7% of the cases. Tracheostoma closure was possible in all except two cases after a mean period ranging between 12 and 28 days. Swallowing results seemed good, with longer recovery time in irradiated than in non-irradiated patients who underwent SCL. Voice quality determined with psychoacoustic methods had acceptable intelligibility.     

The role of supracricoid laryngectomy for glottic carcinoma recurrence after radiotherapy failure: a critical review

Conclusions.In the near future salvage supracricoid laryngectomy (SCL) will be used more extensively for failures of radiotherapy for glottic carcinoma. Objectives. Primary radiotherapy has been used for patients with early glottic carcinomas in northern Europe and North America for more than half a century. Local recurrences after radiotherapy for glottic malignancies occur in 5–25% for T1 carcinomas and in 15–50% for T2 carcinomas. The classic choice as salvage surgery in cases of glottic squamous cell carcinoma recurrence after irradiation failure is total laryngectomy. The development of extended conservation procedures such as SCL has permitted an increasing number of successful partial laryngectomies that save laryngeal functions after radiotherapy failure. SCL allows the creation of a neo-larynx, permitting both swallowing and speech; in most cases the tracheostoma can be closed. Methods. The electronic database Pubmed was searched without publication date limits. Results. Considering available data (103 cases), 84.5% of the cases treated with salvage SCL for irradiation failure did not present a new local recurrence; laryngeal recurrences after salvage SCL (15.5%) were successfully treated with total laryngectomy in 66.7% of the cases. Tracheostoma closure was possible in all except two cases after a mean period ranging between 12 and 28 days. Swallowing results seemed good, with longer recovery time in irradiated than in non-irradiated patients who underwent SCL. Voice quality determined with psychoacoustic methods had acceptable intelligibility.     

Long-term results of radium contact irradiation of laryngeal carcinoma and their relevance in modern therapeutical regimens

BACKGROUND: Despite the fact that it is widely accepted that a second radiogenic carcinoma might occur after radiotherapy of laryngeal carcinomas, there are only a few long-term follow-up studies published yet. METHODS: Between 1973 and 1988 193 patients have been treated by radium contact irradiation because of glottic cancer (Tcis, T1, T2). After the cancer had been diagnosed by biopsy, a partial resection of the thyroid cartilage in the shape of a window 16 x 18 mm was carried out and a self-retaining capsule which harbours the radium was brought into position. RESULTS: 190 (181 men and 9 women) out of 193 patients could be followed up. At the time of investigation 109 patients had already died, 66 intercurrently. The actuarial disease free survival rate 5 and 10 years for Tcis/T1 glottic cancers were 84.6% and 83.6%. For T2 carcinomas a rate of 100% was found respectively. The actuarial overall survival rate was 96.8% after 5 and 93.1% after 10 years for Tcis/T1 carcinomas. The T2 carcinomas revealed an actuarial overall survival rate of 100% after 5 and 10 years. CONCLUSIONS: As the results of radium contact irradiation are not better than those which can be achieved by microsurgery or modern irradiation techniques no indication exists for a radium contact irradiation of glottic laryngeal cancer today.     

Raised EGFR in combination with low cyclin D1 is associated with radioresistance in laryngeal carcinoma cells

Introduction. Radiotherapy is one of the mainstays of treatment for squamous cell carcinoma. Identifying tumour markers able to predict tumour sensitivity to radiotherapy could enable patient/tumour specific treatment targeting and/or dose modification. In a recent study we demonstrated that high levels of EGFR and cyclin D1 were associated with disease recurrence after radiotherapy for patients with T2 laryngeal cancer.¹ The aim of this study was to investigate this relationship in a panel of cell lines derived from laryngeal squamous cell carcinomas (LSCC). Methods. Six LSCC cell lines were exposed to 2Gy of gamma irradiation from a ¹⁴⁷Caesium source. Following irradiation, a clonogenic assay was used to define the relative radiosensitivity (SF2) of each cell line. Western blot analysis, followed by densitometry measurement, was used to determine the relative expression of EGFR and cyclin D1 in each cell line. Results. Levels of EGFR and cyclin D1 were individually not strongly predictive for radiosensitivity. However, cell lines with a combination of high expression of EGFR and low expression of cyclin D1 were found to correlate strongly with a radioresistant phenotype (P = 0.95). Conclusions. This study accords with previous evidence that the cyclin D1/ EGFR axis is important in determining radiation susceptibility. However, in contrast to previous work we found that low, as opposed to high levels of cyclin D1, were associated with radioresistance. Our studies provide an opportunity for functional investigation of the roles of EGFR and cyclin D1 in determining radioresistance in LSCC cells.     

Clinical significance of beta1 integrin expression as a prediction marker for radiotherapy in early glottic carcinoma

OBJECTIVE: To determine the significance of beta1 integrin expression as a prediction marker for the response to radiotherapy in patients with early glottic carcinoma. STUDY DESIGN: Retrospective study in a tertiary referral center. METHODS: Among the T1/T2 glottic carcinoma patients treated with radiotherapy from 1992 to 2002, 52 had more than 2 years of follow-up and available pretreatment biopsy specimens. The immunohistochemical staining was performed for the assay of beta1 integrin expression, and the staining pattern of each was classified as diffuse, localized, or negative. The associations between the patterns of beta1 integrin expression and clinicopathologic parameters, including response to radiotherapy, involvement of the anterior commissure, and grade of histologic differentiation, were evaluated. RESULTS: After radiotherapy, 42 patients remained tumor free, and 10 patients had recurrent or persistent disease. Six (12%) specimens were negative for beta1 integrin expression, 39 (75%) had a localized staining pattern, and 7 (13%) had a diffuse staining pattern. Recurrence rate was significantly higher in the diffuse group (53%) than in the localized (13%) or negative (17%) groups (P=.023). The pattern of beta1 integrin expression was also closely related to histologic differentiation (P=.008), although the association between response to radiotherapy and histologic differentiation was not significant CONCLUSION: The pattern of expression of beta1 integrin, which has been known as a stem cell marker of the epidermis, may be helpful in predicting the response to radiation in patients with early glottic carcinoma.     

Quantitative analysis of voice quality in early glottic laryngeal carcinomas treated with radiotherapy

The quality of voice after radiotherapy is generally considered to be better than that after surgery for early glottic (Tla and Tlb) carcinomas. Studies concerning voice quality after radiotherapy are scarce, and results have been contradictory concerning actual normalization of voice following therapy. This study was designed to compare several voice parameters of patients successfully treated 1–12 years previously with radiotherapy (5750–7000 cGy) for early glottic carcinoma. Parameters involved an age- and sex-matched control group. Results showed that voice quality following radiotherapy was less than normal for maximum vocal intensity, dynamic vocal intensity range, jitter, and mean fundamental frequency. These findings showed that voice following radiotherapy could not be considered normal.     

The Gregorio Marañón Hospital experience with vertical partial laryngectomies

We present a retrospective study of 551 patients treated with conservative surgery for glottic carcinoma at the Gregorio Marañón Hospital between 1962 and 1996. In all, 12% of cases were locally advanced carcinomas. In early-stage carcinomas there were no statistical differences in 5-year survival between those treated by endoscopic laser resection, vertical hemilaryngectomy and radiotherapy. However, tumor recurrence after primary radiotherapy was higher (27%) than with conservative surgery (12%), while the voice preservation rate was significantly higher with surgery (83%) than with radiotherapy (72%). With locally advanced cancer, irradiated patients (to 60 Gy) had a 50% probability of recurrence with a very low chance for salvage by total laryngectomy (5-year survival rate, 38.5%). In contrast, partial laryngectomy could be performed on carefully selected patients, and the results for these patients were comparable to those for smaller lesions (with a 5-year survival rate of 81%).     

Ki-67, p53 and epidermal growth factor receptor expression in early glottic cancer involving the anterior commissure treated with radiotherapy

OBJECTIVE: TNM staging system is not a sufficiently accurate method for predicting the response of an individual patient to a course of radiotherapy. After irradiation, it can become very difficult to assess data obtained by imaging and endoscopy for the diagnosis of both minimal persistent disease and early recurrence. The search for biological parameters that could be used to identify patients who will respond to radiotherapy is crucial. At this study we aimed at evaluating the prognostic significance of immunohistochemical expression of Ki-67, p53 and epidermal growth factor receptor (EGFR) in laryngeal glottic cancer involving the anterior commissure and treated with radiotherapy. METHODS: From January 1995 to August 2005, 24 patients with glottic cancer involving the anterior commissure were primary treated with radiotherapy. Six patients presented with T1a, 12 patients with T1b and 6 patients with T2. Biopsies were taken before the radiotherapy treatment started. Radiotherapy was done with the same technique for all patients using a linear accelerator device with beam energy of 4-MV photons. Immunohistochemical staining was performed using avidine-biotin-peroxidase technique with antibodies to Ki-67, p53 and EGFR. RESULTS: p53 and EGFR positive expression values and labeling indices were greater in radioresistant than in radiosensitive tumors but without significant differences. On the other hand, Ki-67 was expressed in all radiosensitive tumors and Ki-67 labeling indices were significantly higher in radiosensitive tumors than radioresistant tumors (p=0.01). CONCLUSION: We identified overexpression of Ki-67 as predictive marker of radiosensitivity in glottic cancer involving the anterior commissure, with the results showing significant difference between radiosensitive and radioresistant tumors.     

Prognostic value of malignancy grading and DNA measurements in small glottic carcinomas

Thirty-three small glottic carcinomas (T1 and small T2; UICC, 1978) were examined by malignancy grading using the 8-factor system proposed by Jakobsson et al. [Acta radiol. Ther. phys. Biol. 12: 1-8, 1973] and the 4-factor system set up by Glanz and Eichhorn [Hals-Nas.-Ohrenarzt 33: 103-111, 1985]. DNA ploidy, S-phase, and the presence of polyploid cell nuclei were determined. There was no significant difference in malignancy score or DNA values between tumors that recurred after a full course of radiotherapy and those that did not. All but one carcinoma that recurred had polyploid nuclei, in comparison with only 13 of the 22 nonrecurrent tumors. Neither malignancy grading nor DNA measurements seem to predict the clinical course of small glottic carcinomas. Accurate and adequate radiotherapy may be more reliable for local tumor control than tumor character. The extent of the tumor, such as the involvement of the anterior commissure, may be another factor affecting the prognosis.     

Glottische Larynxkarzinome

BACKGROUND: Endoscopic laser resection is one treatment modality for early glottic carcinoma. Benefits are the preservation of laryngeal structure without tracheotomy, the short duration of treatment, low traumatisation and good functional results. METHODS: From 1989 to 1999, 143 patients with an isolated and previously untreated glottic squamous cell carcinoma were treated by CO2 endoscopic laser resection. The tumors were classified as carcinoma in situ (Tis) in seven cases, T1 tumor (T1N0M0) in 91 patients and T2 tumor (T2N0M0) in 45 cases. Median follow-up was 5 years. RESULTS: For the group of Tis and T1 carcinomas, 86 of 98 patients were free of recurrences. The 12 recurrences (12.2%) were treated by repeated laser surgery and laryngectomy (four patients). None of these patients died of tumor related causes. For patients with T2 carcinomas, the overall recurrence rate was 28.9% (13 patients). In six patients, a total laryngectomy had to be performed and one patient died because of tumor recurrence. The relapse free survival estimate using the Kaplan-Meier method was 87% for Tis and T1 carcinomas and 70% for T2 carcinomas. The overall laryngeal preservation rate was 95% for Tis and T1 carcinomas and 85% for T2 tumors. All recurrences occurred within 4 years of primary surgery. CONCLUSION: The results suggest that the oncological outcome after endoscopic laser surgery is comparable to conventional open partial resections.     

Curative radiotherapy for anterior commissure laryngeal carcinoma

There is continuing controversy surrounding the most effective treatment of glottic carcinoma involving the anterior commissure (AC). Surgery has been the preferred method of treatment, since studies previously indicated early tumor invasion of the thyroid cartilage at the AC, thereby assuming less curability by radiotherapy (RT). Subsequent laryngeal anatomic studies and refinement of RT techniques have brought into question the ineffectiveness of curative irradiation. A retrospective review of 174 patients with early-stage glottic carcinoma treated with standard fractionation curative RT revealed 34 patients with T1 and T2 lesions involving the AC. Allowing for a follow-up of at least 3 years, we observed only a 12% (4 of 34 patients) local recurrence rate after RT alone, with excellent voice quality and no major complications related to the irradiation. The 4 local recurrences were controlled by total laryngectomy, although 2 patients developed distant metastatic disease. Radiotherapy represents an effective method of treating T1 squamous cell carcinoma of the glottis with AC involvement. The small number of T2 glottic carcinomas in this study prevents a meaningful conclusion concerning treatment of these lesions.     

CO2-laser treatment of recurrent glottic carcinoma

The records of 23 patients treated by CO₂-laser surgery for recurrent glottic carcinoma after radiotherapy were studied retrospectively to assess treatment results and complications. 15 patients (65%) were cured with one or more laser procedures. The remaining 8 underwent a total laryngectomy for a second or third recurrence. One patient (4%) died of disease. No major complications from C0₂-laser surgery were encountered. It is concluded that C0₂-laser surgery is a safe method of treatment of recurrent glottic carcinoma.     

Radiation therapy in early glottic cancer. Analysis of 177 consecutive cases

Early vocal cord carcinomas (TiS or T1) in a consecutive series of 177 patients treated by primary radiotherapy over a 10-year period 1970-79 at the Department of General Oncology, Radiumhemmet, Karolinska Sjukhuset, were analysed regarding treatment results. In 137 cases the tumours were invasive (T1N0M0) and in 40 cases carcinoma of in situ type (TiS). Patient were treated with cobalt 60 gamma irradiation in fractions of 2 Gy up to a total dose of 64 Gy delivered as split course (CRE=17.8). Minimum follow-up time was 5 years. Tumour recurred in 21 cases (12%). All but 4 patients were rescued by subsequent surgery, giving 98% total survival. Treatment failures after primary radiotherapy were analysed in detail. Failures could not be attributed to treatment irregularities. No difference in pretreatment tumour size was detected when cured patients were compared with patients who relapsed. Biological factors that cause a relative radioresistance are considered to be the main reason for radiotherapy failures in early glottic cancer.     

半导体激光治疗早期喉声门型癌临床分析

目的探讨应用半导体激光手术治疗早期喉声门型癌的效果。方法对1998～2002年在支撑喉镜、显微镜下半导体激光手术治疗31例早期喉声门型癌进行临床分析。31例中原位癌(Tis)3例,T1a为18例,T1b为8例,T2为2例。并进行术前术后嗓音测定分析,术后随访2～5年。结果31例早期喉声门型癌激光手术治疗后,31例均存活。随访3年以上的病例有26例,3年生存率100％(26／26),随访5年的病例有11例,均存活。患者术后比术前嗓音质量提高。结论半导体激光手术治疗早期喉声门型癌疗效可靠,术后喉功能保存好,创伤小,费用低,术后嗓音恢复好,是一种早期喉癌微创治疗的有效方法,值得临床推广应用。     

The utility of second-look operation after laser microresection of glottic carcinoma involving the anterior commissure

Objectives/Hypothesis: Transoral laser microsurgery for the treatment of glottic carcinoma with anterior commissure (A‐com) involvement is associated with a high rate of recurrence. We prospectively evaluated the outcomes of laser microsurgery and the efficacy of second‐look operation in these patients. Study Design: Prospective evaluation. Methods: Twenty‐seven patients with glottic carcinomas involving the A‐com underwent transoral laser microresection. Twenty‐five patients underwent second‐look operations 3 months after laser surgery. Results: After transoral laser microresection, all patients achieved microscopic clear resection margins. Local recurrence was found in 7 of 27 patients (25.9%). Regional recurrence was found in two patients. Patients with recurrences underwent laser re‐resection or neck dissection; four received radiotherapy, two lost their larynxes, and three died of disease. At second‐look operation, early local recurrence was found in two patients, and anterior glottic webs and granulomas causing dysphonia were treated in 8 and 11 patients, respectively. Conclusions: Laser microsurgery is an effective treatment modality in early glottic cancer with A‐com involvement but is still associated with a high rate of recurrence. Second‐look operation may help detect early local recurrence and treat postoperative airway or voice problems.